Methods of delivering pharmaceutical agents

ABSTRACT

Provided are methods of delivering at least one pharmaceutical agent to the central nervous system (CNS) of a subject, methods of treating a neurological disorder or pain in a subject that include administering at least one pharmaceutical agent onto a SEM graft in the skull base of the subject. Also provided are methods of treating a neurological disorder or pain in a subject that include forming a SEM graft in the skull base of the subject and administering at least one pharmaceutical agent onto the SEM graft in the skull base of the subject. Also provided are methods of forming a SEM graft in the skull base of a subject, compositions for administration onto a SEM graft in the skull base or into an endonasal reservoir or endonasal reservoir device in a subject, and devices for administering such compositions onto a SEM graft in the skull base of a subject.

CLAIM OF PRIORITY

The present application is a continuation of U.S. patent applicationSer. No. 14/172,349, filed on Feb. 4, 2014, which is a continuation ofU.S. patent application Ser. No. 13/561,998, filed Jul. 30, 2012, whichclaims the benefit of U.S. Provisional Patent Application No.61/513,069, filed on Jul. 29, 2011, the entire contents of the foregoingare hereby incorporated by reference herein.

TECHNICAL FIELD

This invention relates to methods of delivering pharmaceutical agents tothe central nervous system of a subject, e.g., for treating neurologicaldisorders and pain.

BACKGROUND

Neurological disorders affect more than 20 million patients in the U.S.alone and account for over $400 billion in annual expenditure for boththeir treatment and chronic care (Shoichet et al., Adv. Drug Deliv. Rev.42:81-102, 2000). As the population continues to age, the incidence andhealth care costs associated with neurological disorders are projectedto rise considerably. In 2006, the world-wide prevalence of Alzheimer'sdisease alone was 26.6 million, and this number is expected to quadrupleby 2050 (Brookmeyer et al., Alzheimers Dement. 3:186-191, 2007). Thescale of this disease burden suggests that therapies capable of delayingor treating neurological disorders will translate into enormous costsavings to the global health care system.

The paucity of effective neurological disorder therapies is at leastpartially attributable to the presence of the blood-brain-barrier (BBB).The BBB excludes or prevents many potential therapeutic agents fromreaching the central nervous system (CNS). The BBB performs thisfunction by excluding molecules having specific physical and/orelectrochemical properties, by metabolizing molecules, and by effluxingmolecules. The BBB has been estimated to prevent up to 98% of allpotential neuropharmaceutical agents from reaching the CNS (Cardoso etal., Brain Res. Rev. 64:328-363, 2010). Due to the activity of the BBB,known polar, charged, and macromolecular agents that may be capable oftreating neurological disorders are clinically ineffective due to theirinability to cross the BBB to reach the CNS.

SUMMARY

This invention is based, in part, on the discovery that a semipermeableepithelial membrane (SEM) graft can be successfully placed in the skullbase of a patient. The placement of the SEM graft in this locationallows therapeutic agent(s), placed onto the SEM graft (on the sinus ornasal cavity side), to enter the CNS of the subject.

Thus, provided herein are methods of delivering a (e.g., at least one)pharmaceutical agent to the CNS of a subject. These methods includedirectly administering the pharmaceutical agent onto a SEM graft in theskull base of the subject. In some embodiments, the pharmaceutical agentis administered into an endonasal reservoir or an endonasal reservoirdevice in the subject. In some embodiments, the pharmaceutical agent isdelivered to the brain of the subject.

Also provided are methods of treating a neurological disorder in asubject having a SEM graft in their skull base. These methods includedirectly administering a (e.g., at least one) pharmaceutical agent ontothe SEM graft in the skull base of the subject. In some embodiments, thepharmaceutical agent is administered into an endonasal reservoir. Insome embodiments of any of the methods described herein, thepharmaceutical agent is placed into an endonasal reservoir device in anendogenous sinus tissue of the subject (e.g., an endonasal reservoirdevice previously implanted into the endogenous sinus tissue of thesubject), where the device contains an (e.g., at least one) opening orpermeable surface proximal to the SEM graft in the skull base and thepharmaceutical agent placed in the endonasal reservoir device isadministered onto the SEM graft in the skull base.

Additional methods of treating a neurological disorder in a subject areprovided. These methods include forming a SEM graft in the skull base ofthe subject and administering a (e.g., at least one) pharmaceuticalagent onto the SEM graft in the skull base of the subject. Someembodiments of these methods further include introducing a SEM graftover an endogenous sinus tissue or at a position proximal to the SEMgraft in the skull base, where the SEM graft in the endogenous sinustissue forms an endonasal reservoir. Some embodiments, further includeintroducing or implanting an endonasal reservoir device containing an(e.g., at least one) opening or permeable surface into an endogenoussinus tissue of the subject and placing the pharmaceutical agent intothe endonasal reservoir device, where the opening or permeable surfaceis proximal to the SEM graft in the skull base and the pharmaceuticalagent in the endonasal reservoir device is administered onto the SEMgraft in the skull base.

Also provided are methods of treating pain (e.g., chronic pain) in asubject having a SEM graft in their skull base. These methods includedirectly administering an (e.g., at least one) analgesic onto the SEMgraft in the skull base of the subject. In some embodiments, theanalgesic is administered into an endonasal reservoir. In someembodiments, the analgesic is placed into an endonasal reservoir devicein an endogenous sinus tissue of the subject, where the device containsan (e.g., at least one) opening or permeable surface proximal to the SEMgraft in the skull base and the analgesic placed in the endonasalreservoir device is administered onto the SEM graft in the skull base.

Additional methods of treating pain in a subject are provided. Thesemethods include forming a SEM graft in the skull base of the subject;and administering a (e.g., at least one) analgesic onto the SEM graft inthe skull base of the subject. In some embodiments, the methods furtherinclude introducing a SEM graft over an endogenous sinus tissue or in aposition proximal to the SEM graft in the skull base, where the SEMgraft in the endogenous sinus tissue forms an endonasal reservoir. Insome embodiments, the methods further include introducing an endonasalreservoir device containing an (e.g., at least one) opening or permeablesurface into an endogenous sinus tissue of the subject and placing theanalgesic into the endonasal reservoir device, where the opening orpermeable surface is proximal to the SEM graft in the skull base and theanalgesic in the endonasal reservoir device is administered onto the SEMgraft in the skull base.

In any of the methods described herein, the forming, introducing,placing or administering is performed by an endoscopic procedure (e.g.,an endoscopic procedure through the subject's nasal canal). In any ofthe methods described herein, the forming, introducing, placing, oradministering is performed by an interfacial procedure (e.g., injectionor insertion through the subject's facial tissue), or an intracranialprocedure (e.g., injection or insertion through the subjects cranium).

In some embodiments of any of the methods described herein, the SEMgraft in the skull base and/or the SEM graft in the endogenous sinustissue is formed from an aerodigestive mucosa (e.g., a sinonasal mucosaor a mucosa from the gastrointestinal tract). In some embodiments, theSEM graft in the skull base and/or the SEM graft in the endogenous nasaltissue is formed from a bioengineered mucosal tissue graft. In someembodiments of any of the methods described herein, the SEM graft in theskull base is formed in the posterior frontal table, cribiformplate/ethmoid roof, planum sphenoidale, tuberculum, sella, clivalrecess, clivus, or cervical spine.

In some embodiments of any of the methods described herein, the at leastone pharmaceutical agent or analgesic is formulated as a component of abiodegradable biocompatible polymer. In some embodiments of any of themethods described herein, the biodegradable biocompatible polymer iscationic. In some embodiments of any of the methods described herein,the biodegradable biocompatible polymer is a gel. In some embodiments,the gel is an alginate gel (e.g., sodium alginate), a cellulose-basedgel (e.g., carboxymethyl cellulose or carboxyethyl cellulose), or achitosan-based (e.g., chitosan glycerophosphate; see, e.g., Bleier etal., Am J Rhinol Allergy 23, 76-79, 2009) gel.

In some embodiments of the methods described herein, the pharmaceuticalagent or analgesic is formulated as a liquid. In some embodiments of themethods described herein, the liquid is a thermosetting liquid. In someembodiments of all of the methods described herein, the at least onepharmaceutical agent or analgesic is administered in a volume of 8 mL orless. In some embodiments of the methods described herein, thepharmaceutical agent or analgesic is administered in a sustained-releaseformulation.

In some embodiments of the methods described herein, the pharmaceuticalagent or analgesic has a molecular size of greater than 500 Daltons(e.g., greater than 1 kD, 5 kD, 10 kD, 15 kD, 20 kD, 25 kD, 30 kD, 70kD, or 100 kD, up to about 500, 750, 1000, 1500, 2000, or 2500 kD, e.g.,from 500 D to 500 kD, or from 500 D to 1000 kD), has a net negative ornet positive charge, is a polar molecule, or any combination thereof. Insome embodiments of all of the methods described herein, the at leastone pharmaceutical agent is selected from the group of: achemotherapeutic agent, L-DOPA, carbidopa, an anti-depressant agent, ananti-psychotic agent, donepezil, rivastigmine tartrate, galantamine,memantine, ISIS-SOD1, ISIS-SMN, ISIS-TTR, ELND005, β- or γ-secretaseinhibitors, neurotrophic peptides (e.g., glial cell-derived neurotrophicfactor), nanoparticles, fusion proteins, and viral vectors.

In some embodiments of any of the methods described herein, theneurological disorder is selected from the group of: Parkinson'sdisease, Alzheimer's disease, frontotemporal dementia, a brain cancer(e.g., glioblastoma multiforme, oligodendroglioma, astrocytoma,oligogastrocytoma, ependymoma, medulloblastoma, and meningioma),Huntington's disease, Bell's palsy, stroke, epilepsy, migraine, a sleepdisorder, multiple sclerosis, muscular dystrophy, amyotrophic lateralsclerosis, acute disseminated encephalomyelitis, encephalitis,Creutzfeldt-Jakob disease, meningitis, depression, and schizophrenia.

In some embodiments of any of the methods described herein, theadministering results in a decrease (e.g., an observable, detectable, orsignificant decrease) in the number or the severity, frequency, orduration of one or more symptoms of the neurological disorder. In someembodiments of the methods described herein, the administering resultsin a decrease (e.g., an observable, detectable, or significant decrease)in the severity, frequency, or duration of pain (e.g., pain score) in asubject.

Also provided herein are biocompatible endonasal reservoir devices thatcontain a section of tubing (e.g., catheter tubing) that is connected toa body, where the body has the capacity to contain a volume of a (e.g.,at least one) pharmaceutical composition and contains an (e.g., at leastone) opening or permeable surface, the opening or permeable surface iscapable of releasing the pharmaceutical composition from the body, andthe device is dimensioned to fit within an endogenous sinus tissue ofthe subject. In some embodiments, the tubing has an inner diameterbetween about 0.2 mm and about 5 mm. In some embodiments, the tubing hasa length between about 1.0 cm and about 15 cm. In some embodiments, theend of the tubing that is not connected to the body is closed with aresealable material (e.g., a material containing silicone).

In some embodiments, the body is conical frustrum-shaped, spherical,rectangular, tubular, or ellipsoidal. In some embodiments, the bodycontains an expandable polymer material. In some embodiments, the bodyhas the capacity to contain a volume of 8 mL or less. In someembodiments, the body contains an (e.g., at least one) opening (e.g., atleast one opening with a diameter equal to or less than 1.0 cm²). Insome embodiments, the body contains a (e.g., least one) permeablesurface (e.g., at least one permeable surface with an area equal to orless than 3.0 cm²).

As used herein, the term “delivering” is meant providing atherapeutically effective amount of at least one pharmaceutical agent orcomposition to a subject.

By the phrase “therapeutically effective amount” is meant a dose of apharmaceutical agent or composition that is sufficient to provide anobservable or detectable beneficial physical effect (e.g., an effectthat can be detected, observed, or measured) in a subject. In someembodiments, a therapeutically effective amount of a pharmaceuticalagent decreases (e.g., a significant, detectable, or observabledecrease) in the number or the severity, duration, or frequency of oneof more (e.g., two, three, four, or five) symptoms of a disease (e.g., aneurological disorder) in a subject. In some embodiments, atherapeutically effective amount of an analgesic decreases (e.g., asignificant, detectable, or observable decrease) in the severity,duration, or frequency of pain (e.g., pain score) in a subject.

By the term “pharmaceutical agent” is meant any molecule (e.g., protein(e.g., an antibody, antigen-binding fragment of an antibody, or aderivative or conjugate thereof), nucleic acid, lipid, carbohydrate, orsmall molecule (e.g., inorganic, organic, or mixed inorganic-organicmolecule), or combination thereof) that is administered to a subject inorder to achieve a therapeutic effect. Non-limiting methods ofadministration of pharmaceutical agents are described herein and areknown in the art. Non-limiting examples of formulations ofpharmaceutical agents are described herein and are known in the art. Insome embodiments, the administration of at least one pharmaceuticalagent results in a decrease (e.g., a significant, detectable, orobservable decrease) in the number or the severity, frequency, orduration of one or more symptoms of disease (e.g., a neurologicaldisorder) in a subject. In some embodiments, the administration of atleast one pharmaceutical agent (e.g., an analgesic) results in adecrease (e.g., a significant, detectable, or observable decrease) inthe severity, frequency, or duration of pain (e.g., pain score) in asubject. A wide variety of pharmaceutical agents are known in the artand are described herein.

By the term “analgesic” is meant any molecule that decreases pain in asubject. Non-limiting examples of analgesics are described herein.Additional examples of analgesics are known in the art.

By the term “central nervous system” is meant the brain, the spinalcord, the cerebral spinal fluid (CSF) that surrounds the brain and thespinal cord, and their associated linings (dura, arachnoid, pia mater,and choroid plexus).

By the term “directly administering” is meant placing at least onepharmaceutical agent (e.g., formulated as a component of a solid (e.g.,a powder or polymer), liquid (e.g., a thermosetting liquid), or gel(e.g., a cationic polymer or any of the polymers described herein)) ontoa specific tissue surface (e.g., a SEM graft in the skull base of asubject), into a specific tissue space (e.g., an endonasal reservoir),or into an endonasal reservoir device in a subject.

By the term “skull base” is meant the bony interface between theanterior, middle, or posterior cranial fossae and the tissue structuresimmediately inferior to them. The air-filled sinonasal cavity issituated adjacent to regions of the anterior, middle, or posteriorcranial fossae. The skull base is formed from several layers includingthe nasal mucosa, mucoperiosteal layer, the bony layer of the skullbase, the intracranial dura, and the arachnoid layer, with the arachnoidlayer abutting the intracranial environment (the subarachnoid space).The skull base contains a number of individual subsites extending fromthe posterior wall of the frontal sinus through the clivus, includingthe cervical spine. From the anterior to posterior direction, thesesubsites include: the posterior frontal table, cribiform plate/ethmoidroof, planum sphenoidae, tuberculum, sella, clival recess, or clivus.The lateral limits of the skull base include the lateral extent of thefrontal, ethmoid, or sphenoid sinuses. These anatomical structures areknown in the art and are further described herein.

By the term “semipermeable epithelial membrane” or “SEM” is meant anepithelial tissue (e.g., a heterologous or autologous epithelial tissue)that has an increased (e.g., a detectable, measurable, or significantincrease) permeability for specific classes of molecules (e.g., any ofthe pharmaceutical agents described herein) compared to the permeabilityof the blood-brain-barrier (BBB) for the same classes of molecules. Insome embodiments, the SEM has increased permeability for at least onepharmaceutical agent that has a molecular size of greater than 500 Da(e.g., greater than 600 Da, 700 Da, 800 Da, 900 Da, 1 kDa, 2 kDa, 3 kDa,4 kDa, 5 kDa, 10 kDa, 20 kDa, 30 kDa, 70 kD, or 100 kD), has a netpositive or net negative charge, or is a polar molecule compared to thepermeability of the BBB for the same at least one pharmaceutical agent.The permeability of a SEM can be determined using methods describedherein. Additional methods for determining the permeability of a SEM areknown in the art. Non-limiting examples of SEMs include: sinonasalmucosa, such as nasoseptal epithelial tissue, middle and inferiorturbinate epithelial tissue, anterior septal epithelial tissue, as wellas palatal epithelial tissue. Additional non-limiting examples of SEMsare mucosa from the gastrointestinal tract and bioengineered mucosamembranes. Additional examples of SEMs are known in the art.

In some embodiments, the SEM can be vascularized (e.g., contains atleast one artery or is pedicled on branches of the external or internalcarotid artery system). In some embodiments, the SEM is a nasoseptalepithelial tissue that contains at least one artery. In some embodimentsthe SEM may be composed of a free tissue graft comprised of anyepithelial or endothelial layer or sheet of tissue. One or more SEMs canbe used to form one or more grafts in the skull base of a subject and/orone or more SEMs can be used to form one or more grafts in an endogenoussinus tissue in a subject. Any combination of two or more SEMs can beused in the methods described herein.

By the phrase “SEM graft in the skull base” is meant a structureresulting from a procedure including the removal of a portion of thesinonasal (and/or olfactory) mucosa, mucoperiosteal layer, and the bonylayer in the skull base of a subject, an incision in, removal, ordisplacement of a portion of the intracranial dura and the arachnoidlayer in the skull base of the subject, and the replacement of theexcised intracranial dura and arachnoid layer or placing into or overthe incision in the intracranial dura and arachnoid layer a SEM (e.g.,any of the SEMs described herein). The SEM graft in the skull base canbe located in the roof of the sphenoid sinus (e.g., in the planumsphenoidale, tuberculum, or a sella subsite). Additional sites for theformation of the SEM graft in the skull base are described herein.

By the term “blood-brain-barrier” or “BBB” is meant a layer of cellsthat are physically connected by tight junctions, which surround the CNSand restrict or prevent the passage of molecules or infectious agents tothe CNS. In the lining of the brain (dura and arachnoid) which isdirectly opposed to the skull base, the blood-brain-barrier is locatedin the arachnoid layer. For example, the blood-brain-barrier restrictsor prevents the passage of molecules greater than 500 Da, molecules witha net positive or net negative charge, or polar molecules to the CNS(e.g., the brain or the spinal cord).

By the term “endonasal reservoir” is meant a surgically generatedanatomical site having the capacity to contain a volume of a (e.g., atleast one) one pharmaceutical composition (e.g., a compositioncontaining at least one pharmaceutical agent, such as any of the polymergels described herein) that is defined, in part, by at least twostructures or surfaces: (i) a SEM graft in the skull base (as describedherein), and (ii) a SEM graft in or over an endogenous sinus tissue orin a position proximal to the SEM graft in the skull base. In someembodiments, the space between or bordered by the SEM graft in theendogenous sinus tissue and the SEM graft in the skull base includes apre-existing sinus lumen.

By the term “endonasal reservoir device” is meant a three-dimensionalbiocompatible, synthetic construct that has a section of tubing (e.g.,catheter tubing with an inner diameter of between 0.2 mm to 5 mm) thatis connected to a body (e.g., a conical frustrum-shaped, spherical,rectangular, tubular, or ellipsoidal body) that has the capacity tocontain a volume (e.g., 8 mL or less) of a (e.g., at least one)pharmaceutical composition (e.g., a composition containing at least onepharmaceutical agent, such as any of the polymer gels described herein),where the expandable body has an (e.g., at least one) opening (e.g., anopening with a diameter equal to or less than 1.0 cm²) or a permeablesurface (e.g., area equal to or less than 3.0 cm²) through which thepharmaceutical composition can be released from the interior of the bodyonto a SEM graft in the skull base of a subject. In some embodiments,the body can be made of an expandable material. The body is dimensionedsuch that it fits comfortably within the endogenous sinus tissue of asubject. In embodiments where the body is made of an expandablematerial, the body is designed such that the fully-expanded body (i.e.,the body filled to capacity with the pharmaceutical composition) fitscomfortably in the endogenous sinus tissue of a subject.

The tubing should have a length sufficient to connect the body (placedin an endogenous sinus tissue of a subject) to the sphenoid sinus in thesubject (e.g., between 1.0 cm to 15 cm in length). The end of the tubingthat is not connected to the body can be closed with a resealablematerial (e.g., a polymer or material containing silicon) that can bepunctured by a needle. Endonasal reservoir devices can be constructedusing any of the polymers described herein and any polymers known in theart. Non-limiting additional features and aspects of endonasal reservoirdevices are described herein.

By the term “expandable polymer material” is meant an elastic materialthat is capable of increasing its surface area upon application of force(e.g., hydrodynamic force). In some embodiments, an expandable polymermaterial forms an enclosed three-dimensional shape, where theintroduction of a volume of a substance (e.g., liquid, gel, or solidpharmaceutical composition) into the lumen or interior of thethree-dimensional shape results in an increase in the total surface areaof the polymer material (i.e., results in an increase in the totalvolume of the three-dimensional shape). Non-limiting examples ofexpandable polymer materials are described herein and additionalexamples are known in the art.

By the term “neurological disorder” is meant any disease or conditionthat affects the CNS (e.g., the brain or the spinal cord). In someembodiments, the neurological disorder has one of more of the followingfeatures: unregulated or misregulated cell growth, increased neuronalcell death, increased loss of myelin, pathological protein misfoldingand/or aggregation, a pathological increase or decrease in neurohormoneor neurotransmitter production or turn-over, a pathological increase ordecrease in neurohormone or neurotransmitter receptor activity, apathological increase or decrease in synaptic transmission betweenneurons, and a pathological increase or decrease in neuronalintracellular signaling pathways. In some embodiments, a neurologicaldisorder can also be manifested by one or more of the followingsymptoms: forgetfulness, confusion, difficulty speaking, loss of memory,disorientation, difficulty writing, depression, anxiety, socialwithdrawal, mood swings, irritability, sleeping problems (e.g.,insomnia), wandering, tremor, slowed motion (bradykinesia), rigidmuscles, impaired posture or balance, muscle weakness, loss ofcoordination, headache, seizures, nausea, double vision or blurredvision, lethargy, and overeating or appetite loss. Non-limiting examplesof neurological disorders are known in the art and are described herein.

By the term “endogenous sinus tissue” is meant a tissue present in thesinus of a subject that is proximal to the skull base of the subject.Endogenous sinus tissue includes, without limitation, the tissuespresent in the maxillary sinuses, the frontal sinuses, the ethmoidsinuses, and sphenoid sinuses, as well as the nasal cavity including butnot limited to the septum, nasal floor, inferior, middle, and superiorturbinates.

By the term “endogenous sinus tissue surface” is meant a surface of atissue present in the sinus that is proximal (e.g., anterior to oropposite of) to a SEM graft in the skull base (as described herein). Insome embodiments, the endogenous sinus tissue surface is proximal to aSEM graft present in the planum sphenoidale, tuberculum, or a sellasubsite.

By the term “roughly parallel” is meant the positioning of two separatelinear or approximately-linear (e.g., curved) tissue structures orsurfaces (e.g., in a subject) such that one of the tissue structures orsurfaces faces or is opposite of (e.g., inferior or anterior) the othertissue structure. In some embodiments, one of the two tissue structuresor surfaces is an SEM graft in the skull base and the second of the twotissue structures or surfaces is a SEM placed in an endogenous sinustissue.

By the term “proximal” is meant the positioning of two structures orsurfaces (e.g., an SEM graft in the skull base and an SEM graft in anendogenous sinus tissue surface, or an SEM graft in the skull base andan endonasal reservoir device) such that they are within a closedistance of each other (e.g., one point in the first structure orsurface and one point in the second structure or surface are within atleast 6.0 cm, 5.5 cm, 5.0 cm, 4.5 cm, 4.0 cm, 3.5 cm, 3.0 cm, 2.0 cm,2.5 cm, 2.0 cm, 1.5 cm, 1.0 cm, 0.8 cm, 0.6 cm, 0.5 cm, 0.4 cm, 0.3 cm,0.2 cm, or 0.1 cm of each other).

By the term “endoscopic procedure” is meant a procedure that isperformed, in part, through the use of instrument that allows theexamination or manipulation of tissues in the interior of a hollow organor cavity in the body of a subject. In some embodiments, an endoscopicprocedure is performed to place an SEM graft in the skull base of asubject. In some embodiments, an endoscopic procedure is performed toplace a SEM graft over endogenous sinus tissue or in a position proximal(e.g., roughly parallel) to the SEM graft in the skull base. In someembodiments, the endoscopic procedure involves the removal of portion ofthe nasal mucosa, mucoperiosteal layer, and the bony layer from theskull base of a subject, and an incision in or removal of a portion ofthe intracranial dura and the arachnoid layer in the skull base of asubject. In some embodiments, an endoscopic procedure is performed toresect a SEM (e.g., an autologous SEM, e.g., any of the SEMs describedherein) from a subject. An endoscopic procedure can also be used toadminister at least one pharmaceutical agent or composition onto an SEMgraft in the skull base of a subject, into an endonasal reservoir, orinto a endonasal reservoir device in a subject. Any of the methodsdescribed herein can be performed through an endoscopic procedure.

By the term “interfacial procedure” is meant a procedure that isperformed, in part, through at least one incision or puncture in thefacial tissue of a subject. In some embodiments, an interfacialprocedure is performed to place an SEM graft in the skull base of asubject. In some embodiments, an interfacial procedure is performed toplace a SEM graft over an endogenous sinus tissue or in a positionproximal (e.g., roughly parallel) to the SEM graft in the skull base orto place an endonasal reservoir device in an endogenous sinus tissue ina subject. In some embodiments, the interfacial procedure involves theremoval of portion of the nasal mucosa, mucoperiosteal layer, and thebony layer, and an incision in or removal of a portion of theintracranial dura and the arachnoid layer in the skull base of asubject. In some embodiments, an interfacial procedure is performed toresect a SEM (e.g., an autologous SEM, e.g., any of the SEMs describedherein) from a subject (e.g., a SEM from the nasoseptal flap). Aninterfacial procedure (e.g., injection) can also be used to administerat least one pharmaceutical agent or composition onto an SEM graft inthe skull base of a subject or into an endonasal reservoir or endonasalreservoir device in a subject. Any of the methods described herein canbe performed through an interfacial procedure.

By the term “intracranial procedure” is meant a procedure that isperformed, in part, through at least one incision or puncture in thecranium of a subject.

By the term “sinonasal mucosa” is meant a mucous membrane that lines thesinonasal passage in a subject (e.g., a human).

By the term “biodegradable” is meant a composition (e.g., a molecule orpolymer (e.g., a gel polymer)) that naturally decomposes in a tissue ina subject (e.g., human). In some embodiments, a biodegradablecomposition does not result in the formation of a precipitate in atissue in the subject (e.g., the products of the decomposition arenaturally cleared from the tissue in which the biodegradable compositionis placed, e.g., by mucocilliary clearance) or in an endonasal reservoirdevice placed in a subject. In some embodiments, the products of thedecomposition are excreted by the subject. In some embodiments, thebiodegradable composition is a sustained-release composition (e.g., acomposition having an in vivo half-life of at least 3 days, 4 days, 5days, 6 days, 7 days, 8 days, 10 days, 14 days, 21 days, 1 month, or 2months).

By the term “biocompatible” is meant a composition (e.g., a molecule orpolymer (e.g., a gel polymer)) that does not induce an observable ordetectable immune response or inflammatory response in a subject.Methods for detecting an immune response or an inflammatory response ina subject are described herein. Additional methods for detecting animmune response or an inflammatory response in a subject are known inthe art.

By the term “alginate gel” is meant a semi-solid composition containingat least one algal polysaccharide. A non-limiting example of an alginategel is sodium alginate.

By the term “cellulose-based gel” is meant a semi-solid compositioncontaining at least one form of cellulose. In non-limiting examples, theat least one form of cellulose can be carboxymethyl cellulose orcarboxyethyl cellulose.

By the term “chitosan-based gel” is meant a semi-solid compositioncontaining at least one linear polysaccharide containing β-(1,4)-linkedD-glucosamine and N-acetyl-D-glucosamine. In one non-limitingembodiment, the chitosan-based gel can be chitosan glycerophosphate;see, e.g., Bleier et al., Am J Rhinol Allergy 23, 76-79, 2009.

By the term “thermosetting liquid” is meant a liquid composition thatcan undergo a phase transition to a solid or a semi-solid state (e.g., agel) spontaneously or following exposure to some form of energy (e.g.,vibrational, light, or heat energy). In some embodiments, the phasetransition to a solid or semi-sold state can occur within a tissue(e.g., an endonasal reservoir) or in an endonasal reservoir device in asubject (e.g., a human). Non-limiting examples of thermosetting liquidsare described herein. Additional examples of thermosetting liquids areknown in the art.

By the term “sustained-release formulation” is meant a composition thatis formulated to allow for the continued release of at least onepharmaceutical agent over a period of time. For example, asustained-release formulation may allow for the release of at least onepharmaceutical agent over a period of at least 3 days, 4 days, 5 days, 6days, 7 days, 2 weeks, 3 weeks, 1 month, or 2 months. In someembodiments, the sustained-release formulation may have an in vivohalf-life of at least 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 10days, 14 days, 21 days, 1-month, or 2 months. Examples ofsustained-release formulations are described herein. Additional examplesof sustained-release formulations are known in the art.

By the term “polar molecule” is meant a molecule that has a distributionof electrical charge(s) that results in an electric dipole or multipolemoment. Molecular polarity is dependent on the difference in theelectronegativity between the atoms present in a molecule and theasymmetry of the molecule's structure.

By the term “chemotherapeutic agent” is meant a molecule that can beused to reduce the rate of cancer cell growth or to induce or mediatethe death (e.g., necrosis or apoptosis) of cancer cells in a subject(e.g., a human). In non-limiting examples, a chemotherapeutic agent canbe a small molecule, a protein (e.g., an antibody, an antigen-bindingfragment of an antibody, or a derivative or conjugate thereof), anucleic acid, or any combination thereof. Non-limiting examples ofchemotherapeutic agents include: cyclophosphamide, mechlorethamine,chlorabucil, melphalan, daunorubicin, doxorubicin, epirubicin,idarubicin, mitoxantrone, valrubicin, paclitaxel, docetaxel, etoposide,teniposide, tafluposide, azacitidine, axathioprine, capecitabine,cytarabine, doxifluridine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, tioguanine, bleomycin, carboplatin, cisplatin,oxaliplatin, all-trans retinoic acid, vinblastine, vincristine,vindesine, vinorelbine, and bevacizumab (or an antigen-binding fragmentthereof). Additional examples of chemotherapeutic agents are known inthe art.

By the term “anti-depressant agent” is meant any molecule that can beused to decrease the number of symptoms or decrease the severity,duration, or frequency of one of more symptoms of depression or apersonality/mood disorder in a subject. Non-limiting examples ofanti-depressant agents include selective serotonin reuptake inhibitors(e.g., citalopram, escitalopram, fluoxetine, paroxetine, andsertraline), serotonin-norepinephrine reuptake inhibitors (e.g.,desvenlafaxine, duloxetine, milnacipran, and venlafaxine), noradrenergicand specific serotonergic antidepressants (e.g., mianserin andmirtazapine), norephinephrine reuptake inhibitors (e.g., atomoxetine,mazindol, reboxetine, and viloxazine), norepinephrine-dopamine reuptakeinhibitors (e.g., bupropion), selective serotonin reuptake enhancers(e.g., tianeptine), norephinephrine-dopamine disinhibitors (e.g.,agomelatine), tricyclic antidepressants (e.g., amitriptyline,clomipramine, doxepin, imipramine, and trimipramine), secondary aminetricyclic depressants (e.g., desipramine, nortriptyline, andprotripyline), monoamine oxidase inhibitors (e.g., isocarboxazid,moclobemide, phenelzine, selegiline, and tranylcypromine), buspirone,gepirone, nefazodone, trandospirone, trazodone, bupropion,benzodiazepines, amphetamine, methylphenidate, modafinil, lithium,carbamazepine, sodium valproate, and lamotrigine. Additional examples ofanti-depressant agents are known in the art.

By the term “anti-psychotic agent” is meant any molecule that can beused to decrease the number of symptoms or decrease the severity,duration, or frequency of one of more symptoms of a psychotic disorderin a subject. Non-limiting examples of anti-psychotic agents includerisperidone, olanzapine, and quetiapine. Additional examples ofanti-psychotic agents are known in the art.

By the term “fusion protein” is meant a polypeptide sequence thatcontains a contiguous sequence of amino acids from at least twodifferent endogenous polypeptides.

By the term “nanoparticle” is meant a composite material that has adiameter of between 2 nm and 100 nm in size. A variety of nanoparticlesare known in the art and can be used to deliver a therapeutic agent(e.g., any of the therapeutic agents described herein) to a subject.

By the term “neurotrophic peptide” is meant a protein that has one ormore of the following activities: promotes the growth of developingneurons, promotes the survival or developing neurons, promotes theinitial development of neurons in the central nervous system orperipheral nervous system, and promote regrowth of damaged neurons.Non-limiting examples of neurotrophic peptides include neurotrophins,glial cell-line derived neurotrophic factor family ligands, andneuropoietic cytokines.

By the term “gene therapy vector” is meant any nucleic acid orrecombinant virus used to deliver a nucleic acid to a cell in a subject.Non-limiting examples of gene therapy vectors include recombinantlentiviruses, flaviviruses, herpes viruses, retroviruses, andadenoviruses. Additional examples of gene therapy vectors are known inthe art.

By the phrase “decrease in the number, frequency, duration, or severityof symptoms” is meant a detectable or observable decrease in the numberof symptoms in a subject or a detectable or observable decrease in therecurrence of at least one symptom, decrease in the length of time thatat least one symptom persists in a subject, or a decrease in theintensity of at least one symptom in a subject. Non-limiting examples ofsymptoms of neurological disorders are described herein. Additionalexamples of neurological disorders are known in the art.

By the phrase “decrease in the frequency, duration, or severity of pain”is meant a detectable or observable decrease in the recurrence of pain,decrease in the length of time of pain, or a decrease in the intensityof pain in a subject.

As used herein, a “subject” is a mammal, including a human and adomestic or farm animal (e.g., a horse, mouse, rabbit, pig, sheep, goat,or cow).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

The patent or application file contains at least one drawing (FIGS. 15,17, and 19) executed in color. Copies of this patent or patentapplication publication with color drawings will be provided by theOffice upon request and payment of the necessary fee.

FIG. 1 is a diagram of the human skull indicating the three exemplarylocations (arrows) for placing the SEM graft in the skull base.

FIG. 2 is a diagram of the human skull indicating the CSF circulationpathway (small black arrows) and exemplary locations in the skull basefor placing the SEM graft (thick black lines) near the beginning of theCSF circulation pathway (large black arrow).

FIG. 3 is a diagram depicting a pedicled nasoseptal flap which maycomprise the SEM. A SEM can be harvested, for example, from the middleturbinate and the inferior turbinate.

FIG. 4 is a diagram showing a cruciate incision made in the intracranialdura and arachnoid layer following removal of the nasal mucosa,mucoperiosteal layer, and the bony layer from a section of the skullbase within the sphenoid sinus.

FIG. 5 is a diagram showing the reflection of the flaps of intracranialdura and arachnoid layer following a cruciate incision made in theintracranial dura and arachnoid layer. The reflection of these flapsallows access to the subarachoid space while preventing postoperativearachnoid regrowth.

FIG. 6 is a diagram showing the placement of one SEM graft in the skullbase. The arrows represent the circulation of substance(s) that occurswithin the endogenous sinus tissue of the subject as a result of theciliary motion of the SEM graft in the skull base.

FIG. 7 is a diagram showing the placement of a SEM graft in the skullbase and a SEM graft over the face of the sphenoid sinus proximal to theSEM graft in the skull base thereby creating in endonasal reservoirwhich is partially comprised of the natural sphenoid sinus. The arrowsrepresent the circulation of substance(s) that occurs within theendogenous sinus tissue of the subject as a result of the ciliary motionof the two SEM grafts.

FIG. 8 is a diagram showing the placement of an endonasal reservoirdevice in an endogenous sinus tissue of the subject. In this diagram,the body of the device has a conical frustrum-shape. The diagram showsthe extension of the tubing of the device extending from the body intothe sphenoid sinus.

FIG. 9 shows the suturing of the nasal tissue following placement of anendonasal reservoir device into the endogenous sinus tissue of thesubject sealing it into a submucosal plane.

FIG. 10A-C is two endoscopic images and one MRI image of a human subjectduring different stages of the formation of an SEM graft in the skullbase. FIG. 10A shows an intranasal view of a human brain after removalof the bone and meninges in the skull base (dashed line). FIG. 10B is aintranasal view of the surgical site after placement of a SEM graft overthe surgically created opening in the skull base. FIG. 1C is an MRIimage with an arrow pointing to the site of the healed SEM overlying thesubarachnoid space (the arrow tip indicates the regions depicted inFIGS. 10A and 10B).

FIG. 11 is a schematic diagram of the murine SEM model. In the model,the SEM graft (indicated as “SMM”) is implanted over the CSF filledsubarachnoid space following removal of the bone and underlying meningescontaining the blood brain barrier.

FIG. 12 is a hematoxylin- and eosin-stained cross section of a murinemodel with a SEM graft healed to adjacent bone and meninges with thebasolateral surface communicating with the subarachnoid space.

FIG. 13 is a set of six photographs showing an exemplary heterotopicmucosal grafting technique in a murine model.

FIGS. 14A-B are a pair of photomicrographs. 14A shows a hematoxylin andeosin (H&E) stained section of mucosal graft implant in directcontinuity with underlying brain parenchyma. Note the intact epitheliallayer consisting of pseudostratified columnar epithelium (bar=200 um.14B shows an intact parietal bone for comparison with typical appearanceof the inner and outer cortical tables with their associated diploicspace.

FIG. 15 is a set of nine fluorescent microscopic images demonstratingtransmucosal rhodamine-dextran delivery (bar=1 mm, bregma −1.06 mm).Negative (NEG) and positive (POS) control images represent deliverythrough intact dura or direct parenchymal delivery with no interveningdura or mucosa. Note the filling of the intracranial vasculaturefollowing intravenous (I.V.) delivery with no transvascular diffusionconsistent with an intact blood-brain barrier (evident in highmagnification inset at 40×). A molecular weight-dependent successivereduction in area and intensity of transmucosal delivery is seen between20, 40, and 500 kDa rhodamine-dextran. Bottom row represents matchedbrightfield images demonstrating the mucosal graft stained with theEvans Blue (M.W. 961 Da) used to confirm mucosal graft integrity priorto dosing.

FIG. 16 is a bar graph showing whole brain luminosity (bregma −1.06 mm)directly below the mucosal graft (n=2, *,**=p<0.05). All markersdemonstrated successful diffusion through the mucosal graft after 24 h.As molecular weight increases, there is a trend towards decreased markerdiffusion as calculated by whole brain luminosity (NS). As expectedthere was negligible diffusion through the intact dura and arachnoid dueto the preservation of the blood-CSF barrier (negative control). Therewas a significant increase in delivery in the positive control in whichmarker was exposed directly to the brain after removal of the dura andarachnoid.

FIG. 17 is a set of four fluorescent microscopic images demonstrating anincrease in area and intensity of transmucosal rhodamine-dextrandelivery over time (bar=1 mm, bregma −1.06 mm, 40 kDarhodamine-dextran).

FIG. 18 is a bar graph showing the maximal length of coronal diffusionfrom mucosal graft into the brain by time and molecular weight. Notethat the diffusion path length was dependent both on the duration ofexposure and molecular weight of the marker (n=2). The maximal diffusiondistance at 72 hrs was significantly greater for the 20 kDa marker thanthe 40 or 500 kDa markers (p<0.05).

FIG. 19 is a set of six fluorescent microscopic images demonstratingtransmucosal rhodamine-dextran delivery to the striatum (bregma 1.18 mm,bar=0.5 mm). Diffusion into the right striatum (ipsilateral to mucosalgraft) occurs in a molecular weight dependent fashion whilecontralateral diffusion to the left striatum is negligible.

FIG. 20 is a bar graph showing mean luminosity of the right and leftstriatum demonstrating increased marker diffusion into the rightstriatum (ipsilateral to the mucosal graft) as molecular weightdecreases (n=2). Delivery to the right striatum was significantlygreater than left for the 20 and 40 kDa markers (*,**, p<0.05).

FIG. 21 is a graph showing the number of contralateral turns observedper minute in a 6-hydroxydopamine (6-OHDA) injury Parkinson's Diseasemouse model before or after intraperitoneal injection with apomorphine.

DETAILED DESCRIPTION

The BBB restricts the ability of systemically administered (e.g., orallyor parenterally administered) therapeutic agents to reach the CNS.Provided herein are methods of delivering pharmaceutical agents to theCNS of a subject, e.g., for treating a neurological disorder or pain ina subject.

The methods described herein provide several advantages over thesystemic delivery of pharmaceutical agents for the treatment ofneurological disorders or pain. These advantages can include one or moreof: a decrease in the toxicity or adverse side effects observed innon-targeted tissue (e.g., tissues outside of the CNS) that result fromsystemic delivery of pharmaceutical agent(s), a reduction in the numberof spikes in the dosage of pharmaceutical agents delivered to the CNS(e.g., a reduction in pulsatile dosing), an increase in the dosage ofpharmaceutical agent(s) that can be administered to the subject withoutincurring toxicity or adverse side effects, an increase the in vivo(e.g., levels of pharmaceutical agent(s) in the CNS (e.g. in the CSF) ofa subject, an increase in the efficiency of delivery of pharmaceuticalagent(s) to the CNS of a subject, and an absence of or a reduction inimmunological or inflammatory response to compositions containing atleast one pharmaceutical agent (e.g., compared to systemicallyadministered drugs or implants).

Methods of Forming a SEM Graft in the Skull Base

The methods of delivering at least one pharmaceutical agent to the CNSof a subject and the methods of treating neurological disorders or paindescribed herein utilize or are performed in a subject having a SEMgraft in their skull base, an endonasal reservoir, or a SEM graft intheir skull base and an endonasal reservoir device. Methods of forming aSEM graft in a skull base of a subject, forming an endonasal reservoir,and placing an endonasal reservoir device in a subject's endogenoussinus tissue are described below. The formation (or placement) of a SEMgraft in the skull base, an endonasal reservoir, or a SEM graft and anendonasal reservoir device in a subject allows for the delivery of atleast one (e.g., two, three, or four) pharmaceutical agent through a SEMgraft in the skull base to the CNS.

General Description of Methods

The methods of forming an SEM graft into the skull base of a subjectgenerally include: removing a portion of the nasal mucosa (and/orolfactory mucosa), mucoperiosteal layer, and the bony layer of the skullbase of a subject; making an incision in the intracranial dura and thearachnoid layer in the skull base of the subject; making an incision inand removing or reflecting a position of the intracranial dura and thearachnoid layer in the skull base of the subject; and placing over theincision of the intracranial dura and the arachnoid layer a SEM. In someembodiments, the SEM graft in the skull base is formed by: removing aportion of the nasal mucosa, mucoperiosteal layer, and the bony layer ofthe skull base of a subject; removing a portion of the intracranial duraand the arachnoid layer; and replacing the excised intracranial dura andarachnoid layer with a SEM. The resulting SEM graft in the skull basehas a basolateral side that communicates with the cerebrospinal fluid(CSF) compartment (also known as the subarachnoid space) or directlywith the brain parenchyma.

The methods of forming an SEM graft in the skull base of a subjectdescribed herein can be performed, e.g., via an endoscopic transnasalprocedure, by an interfacial procedure (making at least one puncture orincision into the facial tissue of the subject), or by an intracranialprocedure (making at least one puncture or incision into the cranium ofthe subject). In some embodiments, the endoscopic transasal procedurecan be performed using a rigid or a flexible endoscope introducedthrough a nostril to allow for simultaneous visualization,magnification, and illumination of the surgical site. The surgical sitemay be visualized directly through the eyepiece of the endoscope;however, a digital camera may also be coupled to the endoscope to allowfor projection of an image of the tissue site (e.g., a nasal or sinustissue) onto a video monitor. Instrumentation can be introduced into theipsilateral or contralateral nostril of the patient (e.g., by the sameperson or a second person) to allow for tissue manipulation (asdescribed in detail below) under direct endoscopic view.

Some embodiments of these methods further include forming an endonasalreservoir by introducing a SEM graft over an endogenous sinus tissue orin a position proximal (e.g., roughly parallel) to the SEM graft in theskull base. The resulting endonasal reservoir allows for the storage anddelivery of at least one pharmaceutical agent or a compositioncontaining at least one pharmaceutical agent onto the SEM graft in theskull base. The endonasal reservoir provides an accessible site forredosing (e.g., one or more doses of at least one of any of thepharmaceutical compositions described herein) and drainage ofdegradation products of the at least one pharmaceutical agent or thecomposition containing at least one pharmaceutical agent (e.g., naturalmucocilliary clearance or by lavage of the endonasal reservoir).

In some embodiments, an endonasal reservoir device is placed in anendogenous sinus tissue of a subject with a SEM graft in their skullbase. As described in detail herein, an endonasal reservoir devicecontains a section of tubing (e.g., catheter tubing) that is connectedto a body. The tubing has a length sufficient to extend from thesphenoid sinus to the body of the device located in an endogenous sinustissue of the subject. The body is dimensioned so as to contain a volumeof at least one pharmaceutical composition and contains at least oneopening or permeable surface that allows the release of at least onepharmaceutical composition onto the SEM graft in the skull base of thesubject. Following placement of the device, the at least one opening orpermeable surface of the body is proximally located to the SEM graft inthe skull base. Additional structural and functional features ofendonasal reservoir devices are described herein.

All of the methods described herein can be performed to or on a subjectwithout adversely affecting sinonasal health and function (e.g., withoutsinus or nasal blockage, infection, or inflammation).

Preparation of the Skull Base and Placement of the SEM

The skull base (or cranial base), as is known in the art, is the bonyinterface between the anterior, middle, or posterior cranial fossae andthe structures immediately inferior to them. The air-filled sinonasalcavity is situated adjacent to regions of the anterior, middle, orposterior cranial fossae. Any of these three regions of the skull base(e.g., the anterior, middle, or posterior cranial fossae) can be used asthe site for forming the SEM graft in the skull base (FIG. 1). In someembodiments, the SEM graft in the skull base is formed at a location inthe skull base proximal to the beginning of the cerebrospinal fluid(CSF) circulation pathway (FIG. 2; large black arrow). The SEM can beresected from another tissue in the subject (e.g., a pedicled nasoseptalflap from the tissues shown in FIG. 3). See, e.g., Chiu and Dunn,Otolaryngol Head Neck Surg. 2006 January; 134(1):33-6, incorporatedherein by reference.

The endogenous skull base contains several layers that act to impede thedelivery of pharmaceutical agents from the intranasal cavity to the CNS.These layers include the nasal mucosa with its associated mucoperiosteallayer and/or olfactory mucosa, the bony layer of the skull base, theintracranial dura, and the arachnoid layer (which contains the BBB).Using a variety of instruments designed for intranasal use, these layerscan be resected while maintaining hemostasis. The resection can also beperformed by an interfacial procedure or an intracranial procedure. Theareas of the skull base where tissue resection can be performed includeany individual or combination of subsites extending from the posteriorwall of the frontal sinus through the clivus, including the cervicalspine. Going from the anterior to posterior direction, the potentialsubsites include the posterior frontal table, the cribiformplate/ethmoid roof, planum sphenoidale, tuberculum, sella, clivalrecess, or clivus. The lateral limits of the sites for the placement ofthe SEM include the lateral extent of the frontal, ethmoid, or sphenoidsinuses.

Following removal of a portion of the nasal mucosa (and/or olfactorymucosa), the mucoperiosteal layer, and the bony layer of the skull base(e.g., equal to or less than 0.5 cm², 1 cm², 1.5 cm², 2 cm², 2.5 cm², 3cm², 3.5 cm², 4 cm², 4.5 cm², 5 cm², 6 cm², 7 cm², 8 cm², 10 cm², 12cm², 14 cm², 16 cm², 18 cm², 20 cm², 22 cm², or 25 cm²), a section ofthe intracranial dura and arachnoid layer can be removed (e.g., equal toor less than 0.5 cm², 1 cm², 1.5 cm², 2 cm², 2.5 cm², 3 cm², 3.5 cm², 4cm², 4.5 cm², 5 cm², 6 cm², 7 cm², 8 cm², 10 cm², 12 cm², 14 cm², 16cm², 18 cm², 20 cm², 22 cm², or 25 cm²) or at least one (e.g., two,three, or four) incision (e.g., equal to or less than 0.25 cm, 0.5 cm,0.75 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 6 cm, 7cm, or 8.0 cm) in both the intracranial dura and arachnoid layer can bemade. In some embodiments, a cruciate incision is made in theintracranial dura and arachnoid layer (FIG. 4), and the four sections oftissue (flaps) can be reflected (folded back) prior to the placement ofthe SEM into the created opening in the intracranial dura and arachnoidlayer (FIG. 5). Likewise, in some embodiments three or more incisionscan be made in star-like pattern and the resulting sections of tissue(flaps) can be reflected (folded back) prior to the placement of the SEMinto the created opening in the intracranial dura and arachnoid layer.The use of a cruciate- or star-like incision with dural/arachnoidreflection prevents regrowth of the blood-brain barrier in the subject.

In some embodiments, a section of the intracranial dura and thearachnoid layer is removed, and the SEM is placed into the createdopening in the intracranial dura and arachnoid layer. In someembodiments of these methods, packing or a sponge-like material isplaced over/in the incision or the opening in the intracranial dura andarachnoid layer prior to placement of the SEM graft in the incision oropening.

The removal of the nasal mucosa (and/or olfactory mucosa), themucoperiosteal layer, and the bony layer of the skull base (describedherein), and the incision in or removal of a portion of the intracranialdura and the arachnoid layer (described herein), results in a defect oropening in the BBB that allows communication between the subarachnoidspace and the sinonasal space. The SEM is placed in this defect oropening should be watertight in order to prevent the leakage of CSF intothe sinonasal cavity following the procedure. In order to avoid leakageof CSF, the SEM is preferably placed over the defect or opening in theintracranial dura and the arachnoid layer such that the SEM fullyoverlaps all the boundaries of the defect or opening in the intracranialdura and the arachnoid layer. The methods described herein can furtherinclude the placement of an underlay graft within the epidural space;however, this graft must also have an increased permeability for atleast one pharmaceutical agent (e.g., pharmaceutical agents with a sizegreater than 500 Da or a net positive or net negative charge, or polarpharmaceutical agents) compared to the permeability of the BBB to thesame at least one pharmaceutical agent. The methods described herein canfurther include the placement of an absorbable or non-absorbable nasalpacking (e.g., a sponge, dressing, or balloon) over the SEM graft in theskull base following its placement in the defect or opening in theintracranial dura and the arachnoid layer. In some embodiments the nasalpacking is placed over the SEM graft in the skull base for at least 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks,or 1 month after the SEM has been placed into the incision or opening inthe intracranial dura and arachnoid layer.

In some embodiments, more than one SEM graft can be formed in the skullbase of the subject. For example, a SEM graft in the skull base can beformed on each side of the subject's face.

SEMs

As described herein, a SEM is placed in an opening or incision in theintracranial dura and the arachnoid layer. In some embodiments, the SEMhas one or more of the following features: it has robust wound healingproperties that allow for the water-tight and immunocompetent resealingof the defect or opening in the arachnoid layer and the intracranialdura; it does not induce a local (e.g., endonasal) or systemicinflammatory or immunological response in the subject; and it maintainsits advantageous semipermeable characteristics (e.g., increasedpermeability to at least one pharmaceutical agent as compared to thepermeability of the same at least one pharmaceutical agent in the BBB)that allow for diffusion of at least one pharmaceutical agent from thesinonasal compartment to the CNS (e.g., into the subarachnoid space). Inall of the methods described herein, it is important that the SEM hasincreased permeability to at least one pharmaceutical agent as comparedto the permeability of the same at least one pharmaceutical agent in theBBB.

An SEM can be derived from the same subject (i.e., an autologous SEM),from a different human subject (e.g., a heterologous SEM), or from ananimal (e.g., a xenogenous SEM). In some embodiments, the SEM is anautologous SEM (e.g., from the sinonasal mucosa of the same subject). Anumber of different tissues (e.g., epithelial tissues) can be used as anSEM. In some embodiments, the SEM can be a free, pedicled, ormicrovascular anastomosed flap of tissue. In some embodiments, the SEMis a section of pedicled sinonasal mucosa. In some embodiments, the SEMis formed from a gastrointestinal mucosa or a tissue engineered mucosa.Sinonasal mucosa is known to be several orders of magnitude morepermeable than the BBB. SEMs formed from sinonasal mucosa can bepedicled on branches of the external or internal carotid artery systemand can contain at least one (e.g., two, three, or four) artery.Non-limiting examples of SEMs formed from sinonasal mucosa include asection of mucosa from the nasoseptum, the middle and inferiorturbinate, and the anterior septum. In some embodiments, the SEM isformed from epithelial mucosa from the palate. In desirable embodiments,the SEM is formed from nasoseptal mucosa (also described as a nasoseptalflap; FIG. 3) which is pedicled on the nasoseptal artery. An SEM formedfrom a nasoseptal flap can have a large surface area and a relativelysmall amount of transmembrane efflux proteins (e.g., P-glycoprotein)which can provide for enhanced permeability of at least onepharmaceutical agent (relative to the permeability of the same at leastone pharmaceutical agent in the BBB).

The area of an SEM (e.g., the SEM graft in the skull base or the SEM inan endogenous sinus tissue proximal to the SEM graft in the skull base(described herein)) can have an area equal to or less than 0.25 cm²′ 0.5cm², 0.75 cm², 1 cm², 1.5 cm², 2.0 cm², 2.5 cm², 3.0 cm², 3.5 cm², 4.0cm², 4.5 cm², 5.0 cm², 5.5 cm², 6.0 cm², 6.5 cm², 7.0 cm², 8 cm², 10cm², 12 cm², 14 cm², 16 cm², 18 cm², 20 cm², 22 cm², 24 cm², or 25 cm².

Formation of an Endonasal Reservoir

Also provided herein are methods for forming an endonasal reservoir in asubject. These methods include forming a SEM graft in the skull base ofthe subject (as described herein), introducing a SEM graft over anendogenous sinus tissue or at a position proximal to the SEM graft inthe skull base of the subject, where the introduction of the SEM graftin the endogenous sinus tissue generates an endonasal reservoir. Anendonasal reservoir is defined, in part, by at least two structures orsurfaces: (i) a SEM graft in the skull base (as described herein), and(ii) a SEM graft over an endogenous sinus tissue or in a positionproximal to the SEM graft in the skull base. In some embodiments, thespace between or bordered by the SEM graft in the endogenous sinustissue and the SEM graft in the skull base includes a pre-existing sinuslumen.

One or more pharmaceutical agents or compositions can be administeredinto an endonasal reservoir in a subject. The formed endonasal reservoiris proximal to the SEM graft in the skull base and allows for diffusionof at least one pharmaceutical agent from the endonasal reservoirthrough direct contact with the SEM graft in the skull base into theCNS. In some embodiments, the endonasal reservoir can also contain anaccess port that allows for repeated (e.g., more than one)administration of at least one pharmaceutical agent or composition intothe endonasal reservoir and/or a route of egress for the degradationproducts of the at least one pharmaceutical agent or compositionadministered. In some embodiments, the SEM graft in the skull base andthe endonasal reservoir are formed in a region of the skull base thatallows for unimpeded bilateral diffusion of at least one pharmaceuticalagent or composition, while introducing the at least one pharmaceuticalagent or composition at a point in the ascending CSF flow cycle (e.g.,at a point where the CSF begins to bathe the brainstem, the midbrain,and the bilateral cerebral cortices) (FIG. 2; large black arrow).

In some embodiments, the SEM graft in the skull base and the SEM graftin the endogenous sinus tissue surface can be from the same tissuesource (e.g., the endonasal mucosa of the subject). In some embodiments,the SEM graft in the skull base and the SEM graft in the endogenoussinus tissue surface can be from different tissue sources (e.g., theendonasal mucosa and mucosa from the middle turbinate). The surface areaof the SEM graft in the skull base and the SEM graft in the endogenoussinus tissue surface can have approximately the same area or can havedifferent areas (e.g., the surface area of the SEM graft in the skullbase has a smaller surface area than the SEM graft in the endogenoussinus tissue surface). In some embodiments of all of the methodsdescribed herein, the SEM graft in the endogenous sinus tissue can beintroduced prior to forming a SEM graft in the skull base of the subject(e.g., at a position that is proximal to the SEM graft in the endogenoussinus tissue surface).

In any of the methods described herein, the SEM graft in the skull baseand the SEM in the endogenous sinus tissue surface are positioned suchthat the cilia present in the SEM graft in the skull base and the SEMgraft in the endogenous sinus tissue beat in a lateral to medialdirection and are positioned in a manner that allows for anapproximately circumferential flow of a liquid pharmaceuticalcomposition (e.g., a liquid containing at least one of any of thepharmaceutical agents described herein) in the endonasal reservoir. FIG.6 shows the introduction of a SEM graft in the skull base and the flowpattern resulting from the cilia in the SEM graft in the subject's skullbase. FIG. 7 shows the introduction of a SEM graft in the skull base(upper section) and a SEM graft in the face of the sphenoid sinusproximal to the SEM graft in the skull base (lower section), and theflow pattern resulting from the cilia in the two SEM grafts.

An endonasal reservoir can contain at least one pharmaceutical agent(e.g., any of the pharmaceutical agents described herein). As describedfurther herein, the at least one pharmaceutical agent can beadministered into the endonasal reservoir using a variety of differentmethods described herein and known in the art. The at least onepharmaceutical agent that is administered into an endonasal reservoircan be formulated in a variety of ways: in a liquid (e.g., athermosetting liquid), a biodegradable biocompatible polymer (e.g., agel or solid), or a powder.

In some embodiments, the endonasal reservoir can contain a volume of atleast one pharmaceutical agent or composition containing at least onepharmaceutical agent equal to or less than 0.25 mL, 0.5 mL, 0.75 mL, 1.0mL, 1.5 mL, 2.0 mL, 2.5 mL, 3.0 mL, 3.5 mL, 4.0 mL, 4.5 mL, 5.0 mL, 5.5mL, 6.0 mL, 6.5 mL, 7.0 mL, 7.5 mL, and 8.0 mL. In some embodiments, theendonasal reservoir has a tissue site or outlet (e.g., an opening orshunt) that allows for the direct administration (e.g., endoscopicadministration or injection) of one or more doses of a compositioncontaining at least one pharmaceutical agent (e.g., a liquid, gel, orsolid) or allows for the removal of the degradation products of acomposition containing at least one pharmaceutical agent that waspreviously administered into the endonasal reservoir (e.g., lavage ofthe endonasal reservoir). In some embodiments, a lavage of the endonasalreservoir in the subject is performed prior to the introduction of thenext dose of pharmaceutical composition (e.g., a composition containingat least one pharmaceutical agent) into the endonasal reservoir of asubject. As is known in the art, a lavage may be performed using anysuitable biological buffer (e.g., saline solution).

In some embodiments, more than one endonasal reservoir may be formed ina subject. For example, an endonasal reservoir can be formed in sinustissue on both sides of the face.

Endonasal Reservoir Devices

Also provided herein are endonasal reservoir devices and methods ofintroducing endonasal reservoir devices in a subject. An endonasalreservoir device can be placed into an endogenous sinus tissue of asubject having an SEM graft in their skull base. In some embodiments, anSEM graft is formed in the skull base following the implantation of anendonasal reservoir device in an endogenous sinus tissue of the subject.The combination of a SEM graft in the skull base and the implantation ofan endonasal reservoir device in an endogenous sinus tissue in thesubject allows for the administration of at least one pharmaceuticalagent from the endonasal reservoir device onto the SEM graft in theskull base. Such administration results in the delivery of thepharmaceutical agent(s) in the endonasal reservoir device to the centralnervous system of the subject (e.g., the brain).

An endonasal reservoir device is a three-dimensional biocompatiblesynthetic construct that has a section of tubing (e.g., catheter tubingwith an inner diameter of between 0.2 mm to 5 mm) that is connected to abody that has the capacity to contain a volume of a (e.g., at least one)pharmaceutical composition (e.g., any of the pharmaceutical compositionsdescribed herein), where the expandable body has an (e.g., at least one)opening (e.g., an opening with a diameter equal to or less than 1.0 cm²)or a permeable surface (e.g., a surface equal to or less than 3.0 cm²)through which the pharmaceutical composition can be administered onto aSEM graft in the skull base of a subject.

The tubing of the device should have a length sufficient to connect thebody (placed in an endogenous sinus tissue of a subject) to the sphenoidsinus in the subject. In some embodiments, the tubing of the device hasa length between about 1.0 cm and about 15 cm, about 1.0 cm to about 10cm, about 1.0 cm and about 8.0 cm, about 2.0 cm and about 7.0 cm, about5.0 cm and about 10 cm, about 1.0 cm and about 4.0 cm, about 4.0 cm andabout 8.0 cm, and about 10 cm to about 15 cm). The end of the tubingthat is not connected to the body of the device can be closed with aresealable material (e.g., a polymer or material containing silicon)that can be repeatedly punctured by a needle. Upon placement of thedevice a subject, the end of the tubing that is not connected to thebody can be located in the sphenoid sinus such that a needle introducedthrough the subject's nasal cavity (nostril) can be used to inject atleast one pharmaceutical agent into the tubing of the device and thus,fill the body of the device (located in an endogenous sinus tissue) withthe at least one pharmaceutical agent. Additional details of filling thedevice with at least one pharmaceutical agent (e.g., dosing) aredescribed below.

In different embodiments, the at least one opening or permeable surfaceis circular, ellipsoidal, rectangular, semi-circular, square,triangular, pentagonal, or hexagonal. In some embodiments, the permeablesurface can be composed of a polymeric permeable mesh or a permeablemembrane (e.g., a permeable membrane filter). In some embodiments, theat least one opening has a size equal to or less than 1.5 cm², 1.4 cm²,1.2 cm², 1.0 cm², 0.8 cm², 0.6 cm², 0.4 cm², 0.3 cm², 0.2 cm², or 0.1cm². In some embodiments, the at least one permeable surface has an areaequal to or less than 3.0 cm², 2.8 cm², 2.6 cm², 2.4 cm², 2.2 cm², 2.0cm², 1.8 cm², 1.6 cm², 1.4 cm², 1.2 cm², 1.0 cm², 0.8 cm², or 0.5 cm².The body of the device is placed in the endogenous sinus tissue of thesubject such that the at least one opening or permeable surface of thebody is proximal to the SEM graft in the subject's skull base.

In some embodiments, the body can be made of an expandable material(e.g., a material containing silicone), such that introduction of atleast one pharmaceutical composition into the body of the device resultsin an increase in the volume of the body of the device. In someembodiments, the body or the tubing of the device can contain, at leastin part, silicone, polyethylene, and/or polyetheretherketone. The bodyof the device is dimensioned such that it fits comfortably within theendogenous sinus tissue of a subject (e.g., when empty or when filledwith a volume of a pharmaceutical composition). In embodiments where thebody is made of an expandable material, the body is designed such thatthe fully-expanded body (i.e., the body filled to capacity with thepharmaceutical composition) fits comfortably in the endogenous sinustissue of a subject. The body of the device can have a variety ofdifferent shapes (e.g., conical frustrum-shaped, spherical, rectangular,tubular, or ellipsoidal). The body of the device can contain a volume ofa pharmaceutical agent (e.g., equal to or less than 8.0 mL, 7.5 mL, 7.0mL, 6.5 mL, 6.0 mL, 5.5 mL, 5.0 mL, 4.5 mL, 4.0 mL, 3.5 mL, 3.0 mL, 2.5mL, 2.0 mL, 1.5 mL. or 1.0 mL).

In some embodiments, the endonasal reservoir devices do not containtubing and contain an expandable body that contains at least one openingor permeable membrane (e.g., having any of the features describedabove). In these embodiments, the body is made of resealable materialthat can be repeatedly injected using a syringe (e.g., through aninterfacial procedure). The redosing of these devices can be performedby injecting at least one pharmaceutical composition into the lumen(interior) of the device in the endogenous sinus tissue of the subject.

FIG. 8 shows the placement of an exemplary endonasal reservoir device inan endogenous sinus tissue of a subject with the tubing of the deviceextending from the body into the sphenoid sinus. FIG. 9 shows thesuturing of the nasal tissue following placement of an endonasalreservoir device into the endogenous sinus tissue of the subject,thereby sealing it into the submucosal plane.

Methods of Delivering Pharmaceutical Agents

Provided herein are methods of administering at least one pharmaceuticalagent or composition (e.g., any of the pharmaceutical agents orcompositions described herein) to the CNS of a subject. These methodsinclude directly administering at least one pharmaceutical agent orcomposition containing at least one pharmaceutical agent onto a SEMgraft in the skull base of the subject. In some embodiments, the atleast one pharmaceutical agent or composition is administered into anendonasal reservoir. In some embodiments, the pharmaceutical agent orcomposition is administered into an endonasal reservoir device in anendogenous sinus tissue of the subject that is positioned such that theat least one opening or permeable surface of the body is proximal to theSEM graft in the subject's skull base. In some embodiments, theadministering results in the delivery of at least one pharmaceuticalagent to the brain of the subject.

In some embodiments, the at least one pharmaceutical agent orcomposition can be administered through an endoscopic procedure (e.g.,by directing an endoscopic instrument through the nasal canal of thesubject). In some embodiments, the at least one pharmaceutical agent orcomposition is administered by endoscopically guiding a tube through thenasal canal of the subject into the endonasal reservoir or to the SEMgraft in the skull base, such that a volume of a liquid, gel, or solidpharmaceutical composition containing at least one pharmaceutical agentcan be administered through the tube into the endonasal reservoir oronto the SEM graft in the skull base. In some embodiments, the at leastone pharmaceutical agent or composition can be introduced into anendonasal reservoir device (e.g., injected into the end of the tubinglocated in the sphenoid sinus of a subject or injected directly into thelumen of the body of the device) through an endoscopic procedure orthrough use of a nasal speculum. In some embodiments, the injection ofthe at least one pharmaceutical agent or composition into the tubing ofthe device pushes the agent/composition (via hydrodynamic force) intothe body of the device. The filled body of the device then releases theagent/composition through the at least one opening or permeable surfaceonto the proximally located SEM graft in the skull base of the subject.

In some embodiments, the at least one pharmaceutical agent orcomposition can be administered into the endonasal reservoir, theendonasal reservoir device, or onto the SEM graft in the skull base byinjection through the facial tissue of the subject. In some embodiments,the injection can be performed using a cannula and an imaging device(e.g., MRI or ultrasound) that images the position of the tip of thecannula relative to the SEM graft in the skull base, the endonasalreservoir, or the endonasal reservoir device. In the embodiments thatutilize injection through the facial tissue, the cannula should notpierce the SEM graft in the skull base.

At least one dose (e.g., at least 2, 3, 4, 5, 10, 20, 40, or 60 doses)of a composition containing at least one pharmaceutical agent can beadministered to the subject over time. The subject can be administeredmultiple doses (e.g., two or more doses) of a composition containing atleast one pharmaceutical agent over an extended or chronic treatmentperiod (e.g., for at least 1 week, 2 weeks, 1 month, 2 months, 6 months,1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9years, 10 years, 15 years, 20 years, 25 years, or 30 years). The dosageof the at least one pharmaceutical agent can be adjusted by a healthcare professional (e.g., a physician) based on a number of factorsincluding: the particular pharmaceutical agent(s) administered, thephysical condition of the subject (e.g., weight and the identity andnumber of disorders), and the subject's sex, weight, and age.

Two or more doses of a composition containing at least onepharmaceutical agent can be administered at any frequency of at leastonce a week, once every 2 weeks, once every 3 weeks, once a month, onceevery 2 months, once every 3 months, once every 4 months, once every 5months, or once every 6 months. The frequency of the administration oftwo or more doses of a composition containing at least onepharmaceutical agent will depend on the half-life of the composition invivo. For example, the administration of an additional or the next doseof a pharmaceutical composition containing at least one pharmaceuticalagent can be performed once the immediately prior dose of thecomposition has fully degraded, partially degraded, and/or there is asub-therapeutic amount of the at least one pharmaceutical agentremaining in the subject. In some embodiments, the two of more doses ofa pharmaceutical composition (e.g., any of the pharmaceuticalcompositions described herein) are administered at a frequency thatdecreases or prevents any significant fluctuations in the dosage of theat least one pharmaceutical agent delivered to the CNS of the subject.As described herein, in some embodiments a (e.g., one or more) lavagecan be performed to remove the degradation products of a previouslyadministered dosage of a pharmaceutical composition (e.g., a compositioncontaining at least one pharmaceutical agent) prior to theadministration of the next dosage of the composition. For example, alavage may be performed to remove degradation products from theendonasal reservoir or the endonasal reservoir device prior toadministration of the next dosage of the composition. The number,identity, and/or dosage of pharmaceutical agents delivered to thesubject can be varied during treatment (as described further herein).

The methods provided herein allow for the targeted administration of atleast one pharmaceutical agent to the CNS of the subject, and thereforecan decrease the toxicity or adverse side effects of at least onepharmaceutical agent (e.g., a neuromodulatory or chemotherapeutic agent)in non-targeted tissues (e.g., tissues outside of the CNS). In view ofthe targeted administration provided by the methods described herein, adosage of at least one pharmaceutical agent that induces adverse sideeffects or toxicity when systemically administered to the subject can beadministered to subject's CNS system without inducing toxicity oradverse side effects.

The pharmaceutical agent(s) or composition(s) (e.g., any ofpharmaceutical compositions or agents described herein) can beadministered to any subject (e.g., a female, a male, a child, an adult,a subject greater than 50 years old, a subject greater than 60 yearsold, a subject greater than 70 years old, a subject greater than 80years old). A subject administered the at least one pharmaceutical agentor composition containing at least one pharmaceutical agent can bepreviously diagnosed as having a neurological disorder (e.g., any of theneurological disorders described herein) or identified as being in pain(e.g., having chronic pain). In some embodiments, a subject can beadministered at least one pharmaceutical agent or composition containingat least one pharmaceutical agent within 1 week, 2 weeks, 3 weeks, or 1month of the formation of a SEM graft in the skull base or an endonasalreservoir, or the formation of a SEM graft in the skull base and theplacement of the endonasal reservoir device in an endogenous sinustissue in the subject (e.g., using any of the methods described herein).

The at least one pharmaceutical agent or composition containing at leastone pharmaceutical agent can be administered by a health careprofessional (e.g., a nurse, physician's assistant, a laboratorytechnician, or a physician). The administration of at least onepharmaceutical agent or composition containing at least onepharmaceutical agent can be performed in a clinic (e.g., health careclinic) or out-patient facility, a hospital, or in an assisted-livingfacility (e.g., hospice care center or nursing home).

Pharmaceutical Compositions

Also provided are pharmaceutical compositions containing at least onepharmaceutical agent for use in any of the methods described herein. Thepharmaceutical compositions can be delivered to the CNS of the subjectusing any of the methods described herein. In non-limiting embodiments,the compositions contain at least one pharmaceutical agent with amolecular size of greater than 500 Da (e.g., greater than 600 Da, 700Da, 800 Da, 900 Da, 1 kDa, 2 kDa, 3 kDa, 4 kDa, 5 kDa, 10 kDa, 20 kDa,30 kDa, 70 kD, or 100 kD) or a net positive or net negative charge. Insome embodiments, the compositions contain at least one pharmaceuticalagent that is a polar molecule.

In some embodiments, the at least one pharmaceutical agent present inthe composition decreases unregulated or mis-regulated cell growth(e.g., reduces the rate of cancer cell growth), mediates or inducescancer cell death (e.g., necrosis or apoptosis), decreases proteinmisfolding and/or aggregation, mediates an increase or decrease inneurohormone or neurotransmitter production or turn-over, decreases lossof myelin, reduces neuronal cell death or neuronal loss, reduces loss ofaxons, mediates an increase or decrease in neurohormone orneurotransmitter receptor activity, mediates an increase or decrease insynaptic transmission between neurons, and mediates an increase ordecrease in neuronal intracellular signaling pathways. In somecompositions, the at least pharmaceutical agent is an analgesic.

In some embodiments, the delivery of a composition containing at leastone pharmaceutical agent results in a decrease (e.g., a significant,detectable, or observable decrease) in the number of symptoms or thenumber, frequency, or duration of one or more symptoms of disease (e.g.,a neurological disorder) in a subject. In some non-limiting embodiments,the at least one pharmaceutical agent present in the composition can bea chemotherapeutic agent, L-DOPA, carbidopa, an anti-depressant agent,an anti-psychotic agent, donepezil, rivastigmine tartrate, galantamine,memantine, ISIS-SOD1, ISIS-SMN, ISIS-TTR, ELND005, β- or γ-sectretaseinhibitors, neurotrophic peptides, nanoparticles, fusion proteins, andgene therapy vectors. Additional pharmaceutical agents are known in theart.

Non-limiting examples of chemotherapeutic agents include proteins (e.g.,antibodies, antigen-binding fragments of antibodies, or conjugates orderivatives thereof), nucleic acids, lipids, or small molecules, orcombinations thereof. Non-limiting examples of chemotherapeutic agentsinclude: cyclophosphamide, mechlorethamine, chlorabucil, melphalan,daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone,valrubicin, paclitaxel, docetaxel, etoposide, teniposide, tafluposide,azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine,fluorouracil, gemcitabine, mercaptopurine, methotrexate, tioguanine,bleomycin, carboplatin, cisplatin, oxaliplatin, all-trans retinoic acid,vinblastine, vincristine, vindesine, vinorelbine, and bevacizumab (or anantigen-binding fragment thereof). Additional examples ofchemotherapeutic agents are known in the art.

Non-limiting examples of anti-depressant agents include: selectiveserotonin reuptake inhibitors (e.g., citalopram, escitalopram,fluoxetine, paroxetine, or sertraline), serotonin-norepinephrinereuptake inhibitors (e.g., desvenlafaxine, duloxetine, milnacipran, andvenlafaxine), noradrenergic and specific serotonergic antidepressants(e.g., mianserin and mirtazapine), norephinephrine reuptake inhibitors(e.g., atomoxetine, mazindol, reboxetine, and viloxazine),norepinephrine-dopamine reuptake inhibitors (e.g., bupropion), selectiveserotonin reuptake enhancers (e.g., tianeptine),norephinephrine-dopamine disinhibitors (e.g., agomelatine), tricyclicantidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine,and trimipramine), secondary amine tricyclic depressants (e.g.,desipramine, nortriptyline, and protripyline), monoamine oxidaseinhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline,and tranylcypromine), buspirone, gepirone, nefazodone, trandospirone,trazodone, bupropion, benzodiazepines, amphetamine, methylphenidate,modafinil, lithium, carbamazepine, sodium valproate, and lamotrigine.Non-limiting examples of anti-psychotic agents include risperidone,olanzapine, and quetiapine. Additional examples of anti-depressant andanti-psychotic agents are known in the art.

At least one composition containing at least one pharmaceutical agentcan be formulated using any methods known in the art. In non-limitingexamples, the composition containing at least one pharmaceutical agentis formulated as a liquid (e.g., a thermosetting liquid), as a componentof a solid (e.g., a powder or a biodegradable biocompatible polymer(e.g., a cationic biodegradable biocompatible polymer)), or as acomponent of a gel (e.g., a biodegradable biocompatible polymer). Insome embodiments, the at least composition containing at least onepharmaceutical agent is formulated as a gel selected from the group ofan alginate gel (e.g., sodium alginate), a cellulose-based gel (e.g.,carboxymethyl cellulose or carboxyethyl cellulose), or a chitosan-basedgel (e.g., chitosan glycerophosphate). Additional, non-limiting examplesof drug-eluting polymers that can be used to formulate any of thepharmaceutical compositions described herein include, carrageenan,carboxymethylcellulose, hydroxypropylcellulose, dextran in combinationwith polyvinyl alcohol, dextran in combination with polyacrylic acid,polygalacturonic acid, galacturonic polysaccharide, polysalactic acid,polyglycolic acid, tamarind gum, xanthum gum, cellulose gum, guar gum(carboxymethyl guar), pectin, polyacrylic acid, polymethacrylic acid,N-isopropylpolyacrylomide, polyoxyethylene, polyoxypropylene, pluronicacid, polylactic acid, cyclodextrin, cycloamylose, resilin,polybutadiene, N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer,maleic anhydrate-alkyl vinyl ether, polydepsipeptide,polyhydroxybutyrate, polycaprolactone, polydioxanone, polyethyleneglycol, polyorganophosphazene, polyortho ester, polyvinylpyrrolidone,polylactic-co-glycolic acid (PLGA), polyanhydrides, polysilamine, polyN-vinyl caprolactam, and gellan.

The compositions described herein are not limited to the exemplarypharmaceutical agents described herein. Any pharmaceutical agent thatdemonstrates increased permeability in the SEM graft in the skull basecompared to the permeability of the same molecule in the BBB can beincluded in the compositions described herein and may delivered to theCNS using any of the methods described herein. The pharmaceutical agentsthat can be included in the compositions described herein are notlimited by their biophysical or electrochemical features or by thecomposition of the pharmaceutical agent.

In some embodiments, the at least one pharmaceutical agent is formulatedin a composition that continuously releases the at least onepharmaceutical agent onto the SEM graft in the skull base (e.g., avoidsan initial spike in the release of the at least one pharmaceutical agentonto the SEM graft in the skull base). In some embodiments, thecomposition containing the at least one pharmaceutical agent is asustained-release composition (e.g., allows for the release of the atleast one pharmaceutical agent over a period of time). In someembodiments, the at least one pharmaceutical agent is formulated in acomposition (e.g., a sustained-release formulation) that releases the atleast one pharmaceutical agent onto the SEM graft in the skull base overa period of at least 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2months, or 3 months. In some embodiments, the at least onepharmaceutical agent has an in vivo half-life (e.g., the amount of timebetween the administration of the at least one pharmaceutical agent andthe point in time where 50% of the biological activity of the at leastone pharmaceutical agent is present in the subject) of at least 1 week,2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 9 weeks,10 weeks, 11 weeks, or 3 months.

The at least one pharmaceutical agent can be formulated with one or morepermeation enhancers (e.g., surfactants, bile salts, lipids,cyclodextrins, polymers, and tight junction modifiers) in order toincrease the passage of the pharmaceutical agent(s) across the SEM graftin the skull base into the subarachnoid space. In some embodiments, thepharmaceutical agent(s) are formulated with laurocarnitine. Thepharmaceutical agent(s) can also be formulated using differentosmolarities. For example, pharmaceutical agent(s) can be formulated inan isotonic solution in order to increase the passage of thepharmaceutical agent(s) across the SEM graft in the skull base into thesubarachnoid space. In some embodiments, the pharmaceutical agent(s) areformulated in acidic or basic solutions (e.g., formulated such that thepharmaceutical agent(s) are unionized or the fraction of ionizedpharmaceutical agent present in the composition is reduced). In someembodiments, the pharmaceutical agent(s) are formulated in acidic orbasic solution such that the pharmaceutical agent(s) present in thecomposition have a net negative charge.

In some embodiments, the pharmaceutical agent(s) can be formulated withone or more of: a mucoadhesive agent(s), surface-engineerednanoparticles, efflux transporter inhibitors, and vasoconstrictors. Theaddition of these secondary agents to the formulations can reducemucociliary clearance, prolong the residence time of the pharmaceuticalagent(s) at the delivery site, and increase transport across the SEMgraft in the skull base. For example, formulations includingmucoadhesives, such as acrylic acid derivatives, lectin, and lowmethylated pectin, form a viscous gel upon contact with a SEM, resultingin reduced clearance from the site of administration. Chitosan, acationic mucoadhesive, forms electrostatic interactions with thenegatively-charged surface of epithelial cells to reduce clearance fromthe nasal epithelium. Chitosan has the additional effect of reversiblyopening tight junctions, which increases the rate of transport acrossthe SEM graft in the skull base. In some embodiments, the pharmaceuticalagent(s) are formulated as a micro-emulsion formulation containing amucoadhesive. In some embodiments, the pharmaceutical compositionscontain the pharmaceutical agent(s) and an emulsifying agent (e.g.,castor oil, Cremophor RH40).

In some embodiments, the pharmaceutical agent(s) are formulated assurface-engineered nanoparticles with ligands that bind to cellularstructures present in an SEM. For example, the engineered nanoparticlescan contain the ligand ulex europeus agglutinin I and/or wheat germagglutinin. In some embodiments, the compositions can further contain aninhibitor of P-gp efflux transport protein (e.g., rifampin). In someembodiments, the compositions can further contain a vasoconstrictor(e.g., phenylephrine).

The amount of the at least one pharmaceutical agent that can be presentin a single dose of a pharmaceutical composition can be between 1 mg and800 mg, between 1 mg and 20 mg, between 20 mg and 50 mg, between 50 mgto 100 mg, between 100 mg and 200 mg, between 200 mg and 300 mg, between300 mg and 400 mg, between 400 mg and 500 mg, between 500 mg and 600 mg,between 600 mg and 700 mg, between 700 mg and 800 mg, between 50 mg and500 mg, between 200 mg and 600 mg, and between 400 mg and 800 mg. Thevolume of a dose of a composition (e.g., a solid, liquid, or gel)containing at least one pharmaceutical agent can between 0.1 mL to 10mL, between 0.1 mL to 1 mL, between 1 mL to 2 mL, between 2 mL to 3 mL,between 3 mL to 4 mL, between 4 mL to 5 mL, between 5 mL to 6 mL,between 6 mL to 7 mL, between 7 mL to 8 mL, between 1 mL and 5 mL,between 5 mL and 10 mL, and between 3 mL and 8 mL. As described furtherherein, the volume or dosage of a composition containing at least onepharmaceutical agent can be adjusted by a health care professionalduring the treatment of a subject. In some embodiments, a health careprofessional may also add and/or remove one of more pharmaceuticalagents from the administered composition during treatment.

In some embodiments, the at least one pharmaceutical agent is formulatedin a composition that breaks down into decomposition products that arenaturally cleared from the endonasal tissue or the endonasal reservoir(e.g., the degradation products are soluble in sinus fluid or mucus andare cleared by mucociliary clearance from the sinonasal passages). Insome embodiments, the at least one pharmaceutical agent is formulated ina pharmaceutical composition that breaks down into decompositionproducts that do not stimulate an inflammatory response or an immuneresponse in the subject. In some embodiments, the at least onepharmaceutical agent is formulated in a pharmaceutical composition thatdoes not break down into decomposition products that significantly blockor obstruct the sinonasal passages of the subject. The ability of apharmaceutical composition to block or obstruct the sinonasal passagescan be determined by endoscopic visualization of the subject's sinonasaltissues. The ability of a pharmaceutical composition to block orobstruct the sinonasal passage can also be determined by detecting orobserving one or more symptoms of sinonasal passage blockage orobstruction in the subject (e.g., headache or sinus pressure ordiscomfort). An inflammatory or an immune response in a subject'ssinonasal passages can be determined using methods known in the artincluding: observation or detection of at least one symptom of sinitis(e.g., drainage of a thick, yellow or greenish discharge from the noseor down the back of the throat, nasal obstruction or congestion,difficulty breathing through the nose, pain, tenderness, swelling, orpressure around the eyes, cheeks, nose, or forehead, pain in the upperjaw or teeth, reduced sense of smell and taste, cough, ear pain,headache, sore throat, halitosis, fatigue, and fever). An inflammatoryor an immune response in a subject may also be determined using one ormore diagnostic tests known in the art (e.g., enzyme-linkedimmunosorbence assay (ELISA) for elevated levels of C-reactive protein,interleukin-1β, interleukin-6, interleukin-8, interleukin-10, andTNF-α).

Any of the pharmaceutical compositions containing at least one of any ofthe pharmaceutical agents described herein can be packaged with one ormore additional instruments for delivering the composition onto the SEMgraft in the skull base, into the endonasal reservoir, or into theendonasal reservoir device. Any of the pharmaceutical compositionscontaining at least one of any of the pharmaceutical agents describedherein can also be packaged with instructions for administering thecomposition onto the SEM graft in the skull base, into the endonasalreservoir, or into the endonasal reservoir device in the subject. Forexample, the pharmaceutical compositions may be packed with instructionsthat specify that the pharmaceutical composition be administered to asubject having an SEM graft in their skull base, an endonasal reservoir,or an endonasal reservoir device (e.g., an SEM graft, an endonasalreservoir, or an endonasal reservoir device formed or implanted usingany of the methods described herein).

Methods for Treating Neurological Disorders and Pain

Also provided herein are methods of treating a neurological disorder orpain (e.g., chronic pain) in a subject that has a SEM graft in theirskull base that include directly administering at least onepharmaceutical agent (or at least one composition that contains at leastone pharmaceutical agent) onto the SEM graft in the skull base of thesubject or into an endonasal reservoir in the subject. Also providedherein are methods of treating a neurological disorder or pain in asubject that has both a SEM graft in their skull base and an endonasalreservoir device (as described herein).

Also provided are methods of treating a neurological disorder or pain ina subject that include forming a SEM graft in the skull base of thesubject and administering at least one pharmaceutical agent onto the SEMgraft in the skull base in the subject. Some embodiments of the methodsfurther include introducing a SEM graft over an endogenous sinus tissueor at a position proximal (e.g., roughly parallel) to the SEM graft inthe skull base, where the SEM graft in the endogenous sinus tissue formsan endonasal reservoir. The SEM graft in the endogenous sinus tissue maybe introduced either before or after forming the SEM graft in the skullbase of the subject. Some embodiments of the methods further includeintroducing an endonasal reservoir device in an endogenous sinus tissueand forming an SEM graft in the skull base. In these embodiments, theSEM graft in the skull base can be formed in the skull base of thesubject prior to the introduction of the endonasal reservoir device inthe endogenous sinus tissue, or the endonasal reservoir device can beintroduced into an endogenous sinus tissue prior to the formation of theSEM graft in the skull base of the subject. In these embodiments, the atleast one pharmaceutical agent or composition is placed in the deviceand the agent/composition is released from the at least one opening orpermeable surface of the device's body onto the SEM graft in the skullbase of the subject.

In some embodiments of these methods, the forming of SEM graft in theskull base, the forming of a SEM graft in an endogenous sinus tissuesurface of the subject, the introducing of an endonasal reservoirdevice, the administering of the agent/composition onto the SEM graft inthe skull base, the administering of the agent/composition into theendonasal reservoir, and/or the placing/introducing of theagent/composition into the endonasal reservoir device is performed,e.g., by an endoscopic procedure (e.g., through the nasal canal of thesubject), an interfacial procedure (e.g., injection or surgery), or anintracranial procedure (e.g., injection or surgery). In some embodimentsof any of the methods described herein, the at least one pharmaceuticalagent or at least one composition containing the at least onepharmaceutical agent is administered into an endonasal reservoir orplaced into an endonasal reservoir device. In some embodiments of any ofthe methods described herein, the at least one pharmaceutical agent isdelivered to the brain of the subject.

In some embodiments, the SEM graft in the skull base or the SEM graft inan endogenous sinus tissue is formed from sinonasal mucosa (e.g.,autologous or heterologous sinonasal mucosa). Any of the SEMs describedherein can be used to form the SEM graft in the skull base or the SEMgraft in the endogenous sinus tissue surface without limitation.

Any neurological disorder can be treated using any of the methodsdescribed herein. A neurological disorder is a disease or condition thataffects the central nervous system (e.g., the brain or the spinal cord).Non-limiting examples of neurological disorders have one of more (e.g.,two, three, or four) of the following features: unregulated ormis-regulated cell growth (e.g., a brain cancer), a pathologicalincrease in neuronal cell death (e.g., necrosis or apoptosis), apathological decrease in axon number, pathological protein misfoldingand/or aggregation, a pathological loss of myelin, a pathologicalincrease or decrease in neurohormone or neurotransmitter production orturn-over, a pathological increase or decrease in neurohormone orneurotransmitter receptor activity, a pathological increase or decreasein synaptic transmission between neurons, and a pathological increase ordecrease in neuronal intracellular signaling pathways. Non-limitingexamples of neurological disorders can be manifested or diagnosed by theobservation of one or more (e.g., two, three, or four) of the followingsymptoms: forgetfulness, confusion, difficulty speaking, loss of memory,disorientation, difficulty writing, depression, anxiety, socialwithdrawal, mood swings, irritability, sleeping problems (e.g.,insomnia), wandering, tremor, slowed motion (bradykinesia), rigidmuscles, impaired posture or balance, muscle weakness, loss ofcoordination, headache, seizures, nausea, double vision or blurredvision, lethargy, and overeating or appetite loss. Non-limiting examplesof neurological disorders include: Parkinson's disease, Alzheimer'sdisease, a brain cancer (e.g., glioblastoma multiforme,oligodendroglioma, astrocytoma, oligoastrocytoma, ependymoma,medulloblastoma, or meningioma), Huntington's disease, Bell's palsy,stroke, epilepsy, migraine, a sleep disorder, multiple sclerosis,muscular dystrophy, amyotrophic lateral sclerosis, encephalitis,Creutzfeldt-Jakob disease, meningitis, frontotemporal dementia,schizophrenia, and depression.

Additional non-limiting examples of neurological disorders include: AcidLipase Disease, Acid Maltase Deficiency, Acquired Epileptiform Aphasia,Acute Disseminated Encephalomyelitis, Attention Deficit HyperactivityDisorder, Adie's Syndrome, Adrenoleukodystrophy, Agenesis of the CorpusCallosum, Agnosia, Aicardi Syndrome, Aicardi-Goutieres SyndromeDisorder, Neurological Complications of AIDS, Alexander Disease, Alpers'Disease, Alternating Hemiplegia, Anencephaly, Aneurysm, AngelmanSyndrome, Angiomatosis, Anoxia, Antiphospholipid Syndrome, Aphasia,Apraxia, Arachnoid Cysts, Arachnoiditis, Asperger Syndrome, Ataxia,Ataxia Telangiectasia, Cerebellar or Spinocerebellar Degeneration,Autism, Barth Syndrome, Batten Disease, Becker's Myotonia, Behcet'sDisease, Bell's Palsy, Benign Essential Blepharospasm, BenignIntracranial Hypertension, Bernhardt-Roth Syndrome, Binswanger'sDisease, Bloch-Sulzberger Syndrome, Bradbury-Eggleston Syndrome, SpinalTumors, Brain Injury, Brown-Sequard Syndrome, Bulbospinal MuscularAtrophy, Canavan Disease, Causalgia, Cavernomas, Cavernous Angioma,Central Cervical Cord Syndrome, Central Cord Syndrome, Central PainSyndrome, Central Pontine Myelinolysis, Cephalic Disorders, CeramidaseDeficiency, Cerebellar Degeneration, Cerebellar Hypoplasia, CerebralAneurysm, Cerebral Arteriosclerosis, Cerebral Atrophy, CerebralBeriberi, Cerebral Cavernous Malformation, Cerebral Gigantism, CerebralHypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome (COFS),Chorea, Choreoacanthocytosis, Chronic Inflammatory DemyelinatingPolyneuropathy (CIDP), Chronic Orthostatic Intolerance, Chronic Pain,Cockayne Syndrome Type II, Coffin Lowry Syndrome, Colpocephaly, Coma,Complex Regional Pain Syndrome, Congenital Facial Diplegia, CorticobasalDegeneration, Cranial Arteritis, Craniosynostosis, Cree encephalitis,Creutzfeldt-Jakob Disease, Cumulative Trauma Disorders, Cushing'sSyndrome, Cytomegalic Inclusion Body Disease, Cytomegalovirus Infection,Dandy-Walker Syndrome, Dawson Disease, De Morsier's Syndrome,Dejerine-Klumpke Palsy, Dementia (e.g., mult-infarct, semantic,subcortical, and lewy-body associated dementia), Dentate CerebellarAtaxia, Dentatorubral Atrophy, Dermatomyositis, Devic's Syndrome,Diffuse Sclerosis, Dravet Syndrome, Dysautonomia, Dysgraphia, Dyslexia,Dysphagia, Dyspraxia, Dyssynergia Cerebellaris Myoclonica, DyssynergiaCerebellaris Progressiva, Dystonias, Early Infantile EpilepticEncephalopathy, Empty Sella Syndrome, Encephalitis, EncephalitisLethargica, Encephaloceles, Encephalopathy, Encephalopathy (familialinfantile), Encephalotrigeminal Angiomatosis, Epilepsy, EpilepticHemiplegia, Erb-Duchenne and Dejerine-Klumpke Palsies, Erb's Palsy,Essential Tremor, Extrapontine Myelinolysis, Fabry Disease, Fahr'sSyndrome, Familial Dysautonomia, Familial Hemangioma, FamilialIdiopathic Basal Ganglia Calcification, Familial Periodic Paralyses,Familial Spastic Paralysis, Farber's Disease, Febrile Seizures,Fibromuscular Dysplasia, Fisher Syndrome, Floppy Infant Syndrome,Friedreich's Ataxia, Frontotemporal Dementia, Gangliosidoses, Gaucher'sDisease, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker Disease,Giant Axonal Neuropathy, Giant Cell Arteritis, Giant Cell InclusionDisease, Globoid Cell Leukodystrophy, Glossopharyngeal Neuralgia,Guillain-Barré Syndrome, Hallervorden-Spatz Disease, Head Injury,Headache, Hemicrania Continua, Hemifacial Spasm, Hemiplegia Alterans,Hereditary Neuropathies, Hereditary Spastic Paraplegia, HeredopathiaAtactica Polyneuritiformis, Herpes Zoster, Herpes Zoster Oticus,Hirayama Syndrome, Holmes-Adie syndrome, Holoprosencephaly, HTLV-1Associated Myelopathy, Hughes Syndrome, Huntington's Disease,Hydranencephaly, Hydrocephalus, Normal Pressure Hydrocephalus,Hydromyelia, Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia,Hypoxia, Immune-Mediated Encephalomyelitis, Infantile Hypotonia,Infantile Neuroaxonal Dystrophy, Infantile Phytanic Acid StorageDisease, Infantile Refsum Disease, Infantile Spasms, Iniencephaly,Intracranial Cysts, Intracranial Hypertension, Isaac's Syndrome, JoubertSyndrome, Kearns-Sayre Syndrome, Kennedy's Disease, Kinsbourne syndrome,Kleine-Levin Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay Syndrome(KTS), Klüver-Bucy Syndrome, Korsakoffs Amnesic Syndrome, KrabbeDisease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton MyasthenicSyndrome, Landau-Kleffner Syndrome, Lateral Medullary Syndrome, LearningDisabilities, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-NyhanSyndrome, Leukodystrophy, Levine-Critchley Syndrome, Lewy Body Dementia,Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, NeurologicalSequelae of Lupus, Neurological Complications of Lyme Disease,Machado-Joseph Disease, Macrencephaly, Megalencephaly,Melkersson-Rosenthal Syndrome, Meningitis, Menkes Disease, MeralgiaParesthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine,Miller Fisher Syndrome, Mini Stroke, Moebius Syndrome, Motor NeuronDiseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidoses,Multifocal Motor Neuropathy, Multi-Infarct Dementia, Multiple Sclerosis,Multiple System Atrophy with Orthostatic Hypotension, MuscularDystrophy, Myasthenia Gravis, Myelinoclastic Diffuse Sclerosis,Myoclonic Encephalopathy, Myoclonus, Narcolepsy, Neuroacanthocytosis,Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis,Neuroleptic Malignant Syndrome, Neurological Consequences ofCytomegalovirus Infection, Neurological Manifestations of Pompe Disease,Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal MigrationDisorders, Hereditary Neuropathy, Neurosarcoidosis, Neurosyphilis,Neurotoxicity, Nevus Cavernosus, Niemann-Pick Disease, Normal PressureHydrocephalus, Occipital Neuralgia, Ohtahara Syndrome,Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, OrthostaticHypotension, O'Sullivan-McLeod Syndrome, Overuse Syndrome, PantothenateKinase-Associated Neurodegeneration, Paraneoplastic Syndromes,Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, ParoxysmalHemicrania, Parry-Romberg, Pelizaeus-Merzbacher Disease, Pena Shokeir IISyndrome, Perineural Cysts, Periodic Paralyses, Peripheral Neuropathy,Periventricular Leukomalacia, Persistent Vegetative State, Phytanic AcidStorage Disease, Pick's Disease, Pinched Nerve, Piriformis Syndrome,Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly,Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Post-PolioSyndrome, Primary Lateral Sclerosis, Primary Progressive Aphasia, PrionDiseases, Progressive Locomotor Ataxia, Progressive MultifocalLeukoencephalopathy, Progressive Supranuclear Palsy, Prosopagnosia,Pseudo-Torch syndrome, Pseudotoxoplasmosis syndrome, PseudotumorCerebri, Ramsay Hunt Syndrome I, Ramsay Hunt Syndrome II, Rasmussen'sEncephalitis, Reflex Sympathetic Dystrophy Syndrome, Refsum Disease,Repetitive Motion Disorders, Restless Legs Syndrome,Retrovirus-Associated Myelopathy, Rett Syndrome, Reye's Syndrome,Rheumatic Encephalitis, Riley-Day Syndrome, Saint Vitus Dance, SandhoffDisease, Schilder's Disease, Schizencephaly, Seitelberger Disease,Seizure Disorder, Semantic Dementia, Septo-Optic Dysplasia, SevereMyoclonic Epilepsy, Shingles, Shy-Drager Syndrome, Sjögren's Syndrome,Sleep Apnea, Sotos Syndrome, Spasticity, Spina Bifida, Spinal CordInfarction, Spinal Cord Injury, Spinal Cord Tumors, SpinocerebellarAtrophy, Spinocerebellar Degeneration, Steele-Richardson-OlszewskiSyndrome, Stiff-Person Syndrome, Striatonigral Degeneration, Stroke,Sturge-Weber Syndrome, Subacute Sclerosing Panencephalitis, SubcorticalArteriosclerotic Encephalopathy, SUNCT Headache, Swallowing Disorders,Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis,Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, TabesDorsalis, Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, TetheredSpinal Cord Syndrome, Tic Douloureux, Todd's Paralysis, TouretteSyndrome, Transient Ischemic Attack, Transmissible SpongiformEncephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor,Trigeminal Neuralgia, Tropical Spastic Paraparesis, Troyer Syndrome,Tuberous Sclerosis, Vasculitis Syndromes of the Central and PeripheralNervous Systems, Von Economo's Disease, Von Hippel-Lindau Disease (VHL),Von Recklinghausen's Disease, Wallenberg's Syndrome, Werdnig-HoffmanDisease, Wernicke-Korsakoff Syndrome, West Syndrome, Whipple's Disease,Williams Syndrome, Wilson's Disease, Wolman's Disease, and ZellwegerSyndrome. These disorders are well known in the art, and methods ofdiagnosing them are known. A description and exemplary symptoms of eachof the above neurological disorders are described at the NationalInstitute of Neurological Disorders and Stroke website (address:ninds.nih.gov/index.htm). Additional examples of neurological disordersare known in the art. Additional methods for diagnosing a neurologicalcondition are also known in the art and include without limitation: themini-mental state examination, clinical dementia rating, and BeckDepression Inventory or BDI score.

In some embodiments, the subject has a condition listed in the leftcolumn of following table, and the methods include administering one ormore agents listed in the right column.

Neurological Disorder Pharmaceutical Agent Huntington's DiseaseTetrabenazine, Haloperidol, Clozapine, Clonazepam Multiple SclerosisInterferon beta-1a, Interferon beta-1b, Glatiramer acetate,Mitoxantrone, Natalizumab, Brain Derived Neurotrophic Factor Parkinson'sDisease Glial Derived Neurotrophic Factor, Artane, Cogentin,Carbidopa/levodopa, Pramipexole, Ropinirole, Rotigotine, Amantadine,Entacapone Tolcapone, Selegiline, and Rasagaline Alzheimer's DiseaseNamenda, Razadyne, Reminyl, Exelon, Aricept, Cognex

Any type of pain, such as chronic pain (e.g., nociceptive pain orneuropathic pain), malignant pain, breakthrough pain, allodynia,paresthesia, hyperpathia, complex regional pain syndrome I, complexregional pain syndrome II, phantom limb pain, psychogenic pain,anesthesia dolorosa, and idiopathic pain can be treated using themethods described herein. In the methods of treating pain (e.g., all ofthe embodiments described herein), the at least one pharmaceutical agentadministered is an analgesic or the at least one pharmaceuticalcomposition administered contains an analgesic. Non-limiting examples ofanalgesics are described herein. Additional analgesics are known in theart.

Subjects treated using the methods described herein can have a SEM graftin their skull base, can have both a SEM graft in their skull base and aSEM over an endogenous sinus tissue or in a position proximal to the SEMgraft in the skull base (an endonasal reservoir), or can have both a SEMgraft in their skull base and an endonasal reservoir device placed in anendogenous sinus tissue, such that the at least one opening or permeablesurface of the device's body is located proximal to the SEM graft in theskull base of the subject. In some embodiments, the SEM graft in theskull base, the SEM over an endogenous sinus tissue or in a positionproximal to the SEM graft in the skull base, and the endonasal reservoirdevice are formed/introduced using any of the methods described herein.In some embodiments, a SEM graft in the skull base can be formed, a SEMgraft in an endogenous sinus tissue can be formed, and/or an endonasalreservoir device can be introduced at least 3 days, 1 week, 2 weeks, 3weeks, or 4 weeks prior to administering at least one pharmaceuticalagent to the subject (e.g., administering the at least onepharmaceutical agent onto the SEM graft in the skull base, into theendonasal reservoir, or into the endonasal reservoir device).

In some embodiments, the subject can be a male, female, a child (e.g.,between the age of 1 and 12), a teenager (e.g., between 13 and 19), anadult (e.g., at least 19 years old), at least 50 years old, at least 60years old, at least 70 years old, or at least 80 years old. In someembodiments, the subject can be hospitalized or living in anassisted-living facility (e.g., a nursing home).

In some embodiments, the subject has been previously diagnosed as havinga neurological disorder (e.g., a brain cancer or Parkinson's disease).Methods for the diagnosis of neurological disorders are described hereinand additional methods for diagnosing neurological disorders are knownin the art. In some embodiments, the subject may have been diagnosed ashaving a neurological disorder at least 5 years ago or 10 years ago, ormay have received an alternative form of therapeutic treatment for atleast 5 years or 10 years.

In some embodiments, the subject can be classified or identified ashaving a specific stage or severity of a neurological disorder. Forexample, subjects with Parkinson's disease (PD) can be classified asbeing in stage 1-5 of the disease. Stage one of PD is characterized bythe observation of mild symptoms, such as tremors or shaking in one ofthe limbs, poor posture, loss of balance, and abnormal facialexpressions. Stage two of PD is characterized by bilateral symptoms(affecting both limbs and both sides of the body) and difficultywalking, maintaining balance, and performing normal physical tasks.Stage three of PD is characterized by the inability to walk straight orto stand and a noticeable slowing of physical movements. Stage four ofPD is characterized by rigidity, bradykinesia, and the inability tocomplete day-to-day tasks. Stage four PD subjects often cannot liveindependently. Stage five PD subjects have severe disability in theirphysical movements and usually require constant one-on-one medical ornursing care. A subject identified as being in any one of stages 1-5 ofPD can be treated using the any of the methods described herein.

Alzheimer's disease (AD) patients can also be classified as having mild,moderate, or severe AD. Mild AD is characterized by memory loss forrecent events, difficulty with problem solving, complex tasks, and soundjudgments, changes in personality, difficulty organizing and expressingthoughts, and getting lost and misplacing belongings. Moderate AD ischaracterized by increasingly poor judgment, deepening confusion, evengreater memory loss, the need for help with daily activities, andsignificant changes in personality and behavior. Severe AD ischaracterized by the loss of the ability to communicate coherently, therequirement of daily assistance with personal care, and decreasedphysical abilities (e.g., inability to sit or hold his or her headwithout support). A subject identified as having mild, moderate, orsevere AD can be treated using the any of the methods described herein.

A subject with brain cancer can also be classified as being in stage 1-4of the disease (stage 1 being low severity and stage 4 being the highestseverity). In stage one of a brain cancer, the cancer cells have notinvaded the surrounding tissue. In stage two of a brain cancer, thetumor size is larger and the cancer cells have most likely spread to thesurrounding tissue. In stage three of a brain cancer, the cancer cellslook different from normal cells, the surrounding tissue has becomeaffected, and the tumor is classified as being more aggressive. In stagefour of a brain cancer, the tumor has grown aggressively and the cancercan be difficult to treat. In some embodiments of any of the methodsdescribed herein, the subject can be identified as being in any one ofstages 1-4 of a brain cancer and/or may have previously undergonesurgery to remove all or part of a brain tumor.

In some embodiments, the subject has been identified as having anincreased risk of developing a neurological disorder (e.g., expressionof at least one biomarker or at least one gene sequence in a subjectthat is correlated with the development of a neurological disorder or ahereditary predisposition to developing a neurological disorder (e.g.,familial history of the disease)). A subject can be diagnosed as havinga neurological disorder or can be identified as having an increased riskof developing a neurological disorder by a health care professional(e.g., in a clinical laboratory, a clinic, a hospital, or anassisted-living facility (e.g., a nursing home or a hospice-carecenter)).

In some embodiments, the subject has been previously diagnosed as havingpain (e.g., any of the forms of pain described herein). Methods fordiagnosing or assessing pain in a subject are known in the art. Forexample, a number of methods for scoring pain are known in the art,including, but not limited to: Alder Hey Triage Pain Score, Brief PainInventory (BPI), Dallas Pain Questionnaire, Dolorimeter Pain Index(DPI), Faces Pain Scale, Face Legs Activity Cry Consolability Scale,McGill Pain Questionnaire (MPQ), Descriptor Differential Scale (DDS),Neck Pain and Disability Scale (NPAD), Numerical 11 Point Box (BS-11),Numeric Rating Scale (NRS-11), Roland-Morris Back Pain Questionnaire,Wong-Baker FACES Pain Rating Scale, and Visual Analog Scale (VAS). Insome embodiments, the subject may have received an alternative form ofpain treatment for at least 5 years or 10 years.

A subject can be treated in a hospital, a clinic (e.g., an out-patientclinic or primary care facility), or an assisted-living facility (e.g.,a nursing home or hospice care center). The methods of treatmentdescribed herein can be performed by a health care professional (e.g., anurse, a nursing assistant, a clinical technician, a physician'sassistant, and a physician). The level of skill necessary to perform thetreatment methods described herein will vary depending on the specificmethod performed. For example, administering at least one pharmaceuticalagent to a subject by injection through the facial tissue can beperformed by any health care professional, while the endoscopicadministration or placement of at least one pharmaceutical agent orcomposition according to the methods described herein or the forming ofthe SEM graft in the skull base, the forming of the SEM in an endogenoussinus tissue surface, or the introduction of an endonasal reservoirdevice into an endogenous sinus tissue may require the skill of aphysician or physician's assistant.

One or more doses of at least one of any of the pharmaceutical agents orcompositions described herein can be administered to the subject. The atleast one pharmaceutical agent or composition (e.g., any of thepharmaceutical agents or compositions described herein) can beadministered in any dose or volume, at any frequency, or for anyduration of time (e.g., any treatment period) described herein, in anycombination. The at least one pharmaceutical agent or composition can bein any form (e.g., formulation) described herein. In some embodiments,the at least one pharmaceutical agent or composition is chronicallyadministered to the subject (e.g., administered in two or more dosesover a treatment period (e.g., over at least 1 week, 2 weeks, 1 months,2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years,15 years, 20 years, 25 years, or 30 years). Chronic administration canbe performed until one or more specific therapeutic effects or outcomesis achieved (e.g., any of the therapeutic outcomes described herein) orcan continue as long as the specific therapeutic effect or outcomecontinues to be observed in the subject (e.g., a decrease in the numberor the severity, frequency, or duration of one or more symptoms of aneurological disorder, or a reduction of pain (e.g., reduction in atleast one pain score) in the subject). A determination of the length andfrequency of chronic administration can be made by a health careprofessional based on several factors described herein and known in theart.

As described herein, the two or more doses of the at least onepharmaceutical agent or composition can be administered at any frequency(e.g., a dose at least once a week, a dose at least once every twoweeks, a dose at least one every three weeks, a dose at least once everymonth, a dose at least once every two months, or a dose once every threemonths). In some embodiments, only one dose of at least onechemotherapeutic agent or a composition containing at least onechemotherapeutic agent is administered to the subject. In someembodiments, only two, three, four, or five doses of at least onechemotherapeutic agent or a composition containing at least onechemotherapeutic agent is administered to the subject. In someembodiments, the one or more doses of at least one chemotherapeuticagent or a composition containing at least one chemotherapeutic agent isadministered to the subject before or after a surgical procedure toresect or remove all or part of a brain tumor in the subject. Any formof a brain cancer may be treated using the methods described herein(e.g., a primary or a metastatic brain tumor).

In some embodiments of all of the methods described herein, theadministering of the at least one pharmaceutical agent or compositiondescribed herein is performed by an endoscopic procedure (e.g., throughthe nasal canal of the subject). In some embodiments, the endoscopicprocedure can include the use of a tube that allows the delivery of atleast one pharmaceutical agent or composition (e.g., any of thepharmaceutical agents or compositions described herein) onto a SEM graftin a subject, into an endonasal reservoir, or into an endonasalreservoir device. In some embodiments, a pharmaceutical agent orcomposition is introduced into an endonasal reservoir device byinjecting the agent/composition into the end of the tubing that is notconnected to the device's body, where the end of the tubing notconnected to the device's body is located in the sphenoid sinus. Inthese embodiments, the injection can be performed using an endoscopicprocedure or through the use of a nasal speculum.

In some embodiments, the endoscopic instrument used to administer the atleast one pharmaceutical agent or pharmaceutical composition furtherincludes a light source or other means that allows for the visualizationof the sinus or nasal tissues of the subject (e.g., visualization of theSEM graft in the skull base, the endonasal reservoir, and/or theendonasal reservoir device).

In some embodiments of the methods described herein, the endoscopicprocedure can include the use of an instrument that allows the resectionor manipulation of tissue (e.g., nasal mucosa, the mucoperiosteal layer,the bony layer, the intracranial dura, the arachnoid layer, a SEM, anendogenous sinus tissue proximal (e.g., roughly parallel) to an SEMgraft in the subject) in the body or an incision in a tissue in the body(e.g., nasal mucosa, the mucoperiosteal layer, the intracranial dura,the arachnoid layer, a SEM, and an endogenous sinus tissue roughlyparallel to an SEM graft in the subject). In some embodiments, theendoscopic procedure can include the use of forceps that can grab andhold tissue or a device (e.g., nasal mucosa, the mucoperiosteal layer,the bony layer, an excised SEM (e.g., an autologous SEM), a folded backor excised section of the intracranial dura and/or arachnoid layer, anendogenous sinus tissue proximal to an SEM graft in the subject, or anendonasal reservoir device), and can be used to place a SEM graft in theskull base of a subject, place a SEM graft into an endogenous sinustissue surface, or place an endonasal reservoir device in the subject.

In some embodiments the administering of the at least one pharmaceuticalagent or pharmaceutical composition described herein is performed by aninterfacial procedure (e.g., by injection). In some embodiments of thesemethods, the endonasal tissue of the subject is imaged during theinjection procedure, such that the tip of a cannula is positionedproximal (e.g., within 0.1 to 0.5 cm) to the SEM graft in the skullbase, positioned in the endonasal reservoir (e.g., in the center of theendonasal reservoir), or positioned in the interior of the body of theendonasal reservoir device during the injection of the at least onepharmaceutical agent or composition. In some embodiments of thesemethods, the cannula preferably does not contact the SEM graft in theskull base. In some embodiments of all the methods described herein, thesubject is sedated (e.g., mild sedation) or anesthetized (e.g., localfacial or nasal anesthetization) prior and/or during the administrationof the at least one pharmaceutical agent or pharmaceutical composition.In some embodiments, at least one sedative or anesthetic agent isadministered to the subject prior to or during the administration of theat least one pharmaceutical agent or pharmaceutical composition. The atleast one sedative or anesthetic agent may be formulated using anymethods known in the art (e.g., a gas, a liquid for injection (e.g.,intramuscular, intravenous, intraarterial, or intracranial injection)).

In some embodiments of all the methods described herein, the subject maybe administered two or more doses (e.g., chronic administration) of atleast one of any of the pharmaceutical agents or compositions describedherein. As described herein, the at least one pharmaceutical compositionor agent administered can decompose in the body into degradationproducts (e.g., insoluble or partially insoluble degradation products)that are not naturally cleared by mucociliary clearance from theendonasal passages of the subject. Therefore, some embodiments of themethods described herein further include lavaging the endonasal tissue(e.g., lavaging the endonasal reservoir in the subject) or the endonasalreservoir device placed in the subject prior to the administration of anadditional or second dose of a pharmaceutical composition. As is knownin the art, lavage of a body cavity or tissue may be performed using anybiocompatible and/or homeostatic solution (a lavage fluid, e.g.,saline). In some embodiments, a lavage of the endonasal cavity in asubject may be performed endoscopically by inserting an instrumentthrough the nasal canal of a subject into the endonasal cavity of thesubject. This instrument can be equipped with tubing which allows theintroduction of a biocompatible and/or homeostatic solution into theendonasal cavity or the endonasal reservoir. In some embodiments, thelavage of the endonasal reservoir device can be performed by injectingand subsequently removing a biocompatible and/or homeostatic solutioninto and out of the body of the device. For example, the lavage of thedevice can be performed by injecting and subsequently removing thebiocompatible and/or homeostatic lavage solution through the tubing ofthe device (e.g., through the end of the tubing that is not connected tothe device's body, e.g., located in the sphenoid sinus).

The instrument used to perform the lavage can also be equipped with anempty tube connected to a vacuum apparatus to allow removal of thebiocompatible and/or homeostatic solution containing one of more of thedegradation products. As is known in the art, the volume of the lavagefluid utilized in these methods may vary and can readily be determinedby a health care professional during the procedure. A lavage may beperformed prior to the administration of each dosage of the at least onepharmaceutical agent or composition, or a lavage can be performed priorto every other administration of a dosage of the at least onepharmaceutical agent or composition. In some embodiments, a lavage canbe performed at any individual administration in a chronic treatmentregime upon a determination by a health care profession that anaccumulation of degradation products is present in a subject's nasal orsinus tissue, endonasal reservoir, or endonasal reservoir device (e.g.,upon observation or detection of one of more symptoms of nasal/sinusblockage or occlusion (e.g., by endoscopy, computed tomography, andmagnetic resonance imaging), upon observation or detection of one ofmore symptoms of sinitis, or upon observation or detection of one ofmore symptoms of inflammation or infection in the nasal/sinus cavity oran endonasal reservoir in the subject).

As described herein, the methods of treatment described herein canresult in a decrease (e.g., a significant, observable, or detectabledecrease) in the number or the severity, frequency, or duration of atleast one symptom of a neurological disorder in a subject. As is knownin the art, the symptoms of individual neurological disorders candiffer. A number of common symptoms of individual neurological disordersare described herein. These symptoms of neurological disorders (as wellas any other symptoms known in the art) can be detected and observed byhealth care professionals. The efficacy of treatment provided by any ofthe methods described herein can be determined by a health careprofessional by observing or detecting a decrease in the number or theseverity, frequency, or duration of at least one symptom of aneurological disorder in a subject receiving treatment (e.g., ascompared to the number or the severity, frequency, or duration ofsymptoms in the same subject prior to treatment or the number or theseverity, frequency, or duration of symptoms in another subject havingthe same neurological disorder but not receiving treatment). In someembodiments, the administering results in an increase (e.g., anobservable or detectable increase) in cognitive function or memory in asubject (e.g., a subject having Alzheimer's disease). In someembodiments, the administering results in a decrease (e.g., anobservable or detectable decrease) in the rate of loss of neurons and/orsynapses in the cerebral cortex or subcortical regions in the brain of asubject having Alzheimer's disease or in an animal model of Alzheimer'sdisease (e.g., as compared to the rate of loss of neurons and/orsynapses in the cerebral cortex or subcortical regions of a subjecthaving Alzheimer's disease or an animal model of Alzheimer's disease notreceiving treatment or receiving a different therapeutic treatment). Insome embodiments, the administering results in a decrease (e.g., anobservable or detectable decrease) in the amount of amyloid plaquesand/or neurofibrillary tangles or the rate of formation of amyloidplaques and/or neurofibrillary tangles in the cerebral cortex orsubcortical regions in the brain of a subject having Alzheimer's diseaseor in an animal model of Alzheimer's disease (e.g., as compared to theamount of amyloid plaques and/or neurofibrillary tangles or the rate offormation of amyloid plaques and/or neurofibrillary tangles in thecerebral cortex or subcortical regions in the brain of a subject havingAlzheimer's disease or an animal model of Alzheimer's disease notreceiving treatment or receiving a different therapeutic treatment).

In some embodiments, the administering results in a decrease (e.g., adetectable or observable decrease) in one or more symptoms ofParkinson's disease in a subject, e.g., decreased tremor, bradykinesia,and/or rigidity (e.g., as compared to the same subject prior totreatment or another subject having Parkinson's disease but notreceiving treatment). In some embodiments, the administering results inone or more of the following effects: a decrease (e.g., a significant,observable, or detectable decrease) in unregulated or mis-regulated cellgrowth (e.g., cancer cell growth), an increase (e.g., a significant,observable, or detectable increase) in cancer cell death (e.g., necrosisor apoptosis), a decrease in neuron cell death (e.g., apoptosis ornecrosis), a decrease in the loss of axons and/or dendrites or the rateof the loss of axons and/or dendrites, a decrease in protein misfoldingand/or aggregation (e.g., β-amyloid mis-folding or aggregation), anincrease or decrease in neurohormone or neurotransmitter production orturn-over, an increase or decrease in neurohormone or neurotransmitterreceptor activity, an increase or decrease in synaptic transmissionbetween neurons, and an increase or decrease in neuronal intracellularsignaling pathways.

As described herein, the methods of treating pain described herein canresult in a decrease (e.g., a significant, observable, or detectabledecrease) in the severity, frequency, or duration of pain in a subject.As is known in the art, there are a variety of different causes andtypes of pain. Different pain scoring scales have been developed inorder to allow health care professionals to quantitate pain in subjects.The efficacy of pain treatment provided by the methods described hereincan be determined by a health care professional by observing ordetecting a decrease in the severity, frequency, or duration of pain(e.g., pain score) in a subject receiving treatment (e.g., as comparedto the severity, frequency, or duration of pain (e.g., pain score) inthe same subject prior to treatment or the severity, frequency, orduration of pain in another subject having the etiology (e.g., caused bythe same disease or disorder) but not receiving treatment).

In some embodiments of any of the methods described herein, the subjectcan be administered one or more additional therapeutic agents.Non-limiting examples of one or more additional therapeutic agents thatcan be administered include sedatives and analgesics. Non-limitingexamples of sedatives include: barbituates (e.g., amobarbital,pentobarbital, secobarbital, and phenobarbital), benzodiazepines (e.g.,clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam,nitrazepam, oxazepam, traizolam, temazepam, chlordiazepoxide,alprazolam), and anti-histamines (e.g., diphenhydramine, dimenhydrinate,doxylamine, and promethazine). Non-limiting examples of analgesicsinclude: opiates (e.g., morphine, codeine, thebaine, and papverine),non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid,diflusinal, salsalate, ibuprofen, naproxen, fenoprofen, ketoprofen,flurbiprofen, oxaprozin, loxoprofen, indomethacin, sulindac, etodolac,ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam,droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid,flufenamic acid, licofelone, and tolfenamic acid), and COX-2 inhibitorscelecoxib, etoricoxib, and firocoxib).

The methods described herein provide for the treatment of a neurologicaldisease or pain by the targeted delivery of at least one pharmaceuticalagent (e.g., analgesic) or composition (e.g., composition containing analagesic) to the CNS of a subject. In some embodiments, the methodsdecrease (e.g., an observable or detectable decrease) or avoid thetoxicity or adverse effects that are observed when the samepharmaceutical agent(s) or composition(s) is administered systemically(e.g., to a majority of the tissues in the subject). In someembodiments, the methods provided herein allow for an increased dosageof at least one pharmaceutical agent to be administered to the subject(e.g., a dosage that is greater than the maximum sub-toxic dosage thatcan be administered systemically to a subject). In some embodiments, themethods eliminate the variability in dosage levels of at least onepharmaceutical agent in the subject (e.g., as a result of subjectnon-compliance with administration schedules). In some embodiments, themethods reduce the number of spikes in the level of at least onepharmaceutical agent in the CNS of a subject compared to the number ofspikes in the level of at least one pharmaceutical agent in the CNS whenthe at least one pharmaceutical agent is administered orally or byintramuscular, intravenous, intraarterial, or intracranial injection.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

Example 1 Exemplary Surgical Procedure in a Human

An endoscopic procedure was performed on a subject having a brain tumor.In this procedure, the tumor and a section of bone and the meninges wereremoved from the skull base of the subject (FIG. 10A). A SEM graft wasplaced over the opening generated following the removal of the tumor,bone, and the meninges from the skull base (FIG. 10B). The SEM graftplaced over the opening in the bone and meninges in the skull basehealed to prevent leakage of the CSF from the subarachnoid space (FIG.10C).

Example 2 Transport of Molecules Across an SEM Graft in a Mouse Model

Experiments were performed in mice to demonstrate that theadministration of agents onto an SEM graft over the skull of a mouseresults in delivery of the agents to the central nervous system of themouse.

Heterotopic mucosal grafting surgery was performed in adult mice priorto the administration of a test agent to the mice, as shown in FIG. 13.As shown in panel 1, a dural sparing 3 mm parasagittal craniotomy wasperformed over the right parietal bone posterior to the sagittal suture.As shown in panel 2, the dura and arachnoid were reflected using a smallaliquot of vet bond. In panel 3, the septum was harvested from a donormouse en bloc. Panel 4, the mucosa of the donor mouse was implanted overthe craniotomy site (e.g., an SEM graft) and the skin was closed.

Histologic analysis showed that engrafting was complete after 1 week ofhealing providing an acceptable time frame to initiate marker exposure(FIG. 12).

In Panel 5, after one week the mucosal graft was exposed followingreflection of the skin flaps. In Panel 6, a 100 uL reservoir (a plasticcuff) was implanted over the mucosal graft and affixed to the skull withdental cement. The reservoir was then used to dose the graft with thedesired solution, see FIG. 11. Graft integrity was verified using Evansblue dye, a common stain for epithelial barrier integrity; the abilityof the graft to inhibit parenchymal staining was a reliable marker forgraft integrity and complete graft healing. All specimens were examinedunder brightfield microscopy to ensure graft integrity prior tofluorescent analysis.

One hundred microliters of Fluorescein sodium (FI Na) or FITC-dextran(500 μg/ml) having an average molecular weight of 10, 20, 40, or 70 kDawere applied to the SEM graft formed over the skull. Individual micewere sacrificed at 30, 60, 120, or 240 minutes or 12-72 hours afterdosing. Tissue sections were fixed using a perfusion cocktail of 4%paraformaldehyde, 1% Evans Blue (EB), and 0.01% Hoechst as described bydel Valle et al. (J. Neurosci. Methods 174:42-49, 2008).

The graft was centered around bregma −1.5 mm and diffusion wasdetermined at 3 coronal sections to capture striatal diffusion (bregma1.18 mm), immediate submucosal diffusion (bregma −1.06 mm), andsubstantia nigra diffusion (bregma −2.80 mm). Delivery was calculated bycreating a weighted average of the intensity of fluorescent stainingover the total area of marker diffusion (luminosity score). The maximaldiffusion distance from the center of the graft was also calculatedusing standard image processing software.

The findings demonstrated that, although diffusion was limited over theshorter time course, at 12-72 hours the mucosal graft technique wascapable of reproducible high molecular weight marker delivery up to 500kDa directly into the CNS. The luminosity score and maximal diffusiondistance followed a predictable pattern with improved delivery asmolecular weight decreased and exposure time increased (FIGS. 15-18).The data demonstrates successful marker delivery to the striatumipsilateral to the mucosal graft (right side) for the 20 and 40 kDarhodamine-dextran markers. Delivery to the ipsilateral striatum with the500 kDa marker and contralateral striatum with all markers wasnegligible (FIGS. 19 and 20). Delivery to the substantia nigra wasnegligible for all markers.

Example 3 Phenotypic Effect of Agent Delivery to the Central NervousSystem Using an SEM Graft

Additional experiments were performed to determine whetheradministration of an agent directly onto a SEM graft over the skullresulted in a phenotypic effect in a mouse model. These experiments werebased on the observation of a particular behavioral pattern in aParkinson's Disease mouse model following the administration ofapomorphine. Successful administration of apomorphine to the centralnervous system in this mouse model (via direct administration onto a SEMgraft formed over the skull) was manifested by rotational behavior inthe mice. The details of these experiments are described below.

Experimental Design

The mice underwent unilateral striatal 6-hydroxydopamine (6-OHDA)injection (3.2 μg/μL, 0.5 μL/min×4 min) according to Francardo et al.(Neurobiol. Dis. 42:327-340, 2011). Two-week post-injury mice underwenttesting with apomorphine (300 μL, 0.065 mg/mL, t^(1/2)30 −40 min) viasingle bolus IP injection or continuous administration onto a SEM graftover the skull via a drug-eluting hydrogel. The placement of a SEM graftover the skull of the mice was performed as described above. Theduration of rotational behavior was determined in the treated mice.

Quantification of Rotation

The position of the mice was recorded by a camera (while they movefreely in an arena). The number of contralateral rotations per minutewas quantified using a custom analysis program written in Matlab andC++. Statistical analyses were performed using a Student's t-test tocompare results between treatment groups (Stata v6.0).

Results

Mice intraperitoneally administered apomorphine as described above wereshown to have increased rotational behavior (FIG. 21). Based on thesedata and the above described data, a more rapid onset and prolongationof rotational behavior is expected for mice administered apomorphineacross an SEM graft over the skull compared to mice administeredapomorphine by intraperitoneal injection.

Example 4 Neuroprotective Effect of Agents Delivered Across a SEM Graft

Additional experiments will be performed to determine whether deliveryof agents to the central nervous system through a SEM graft over theskull will result in a neuroprotective effect in mice. These experimentswill be performed as described below.

Experimental Design

Aged (8-month old) mice will be assigned to groups listed in Table 1.Treatment with 6-OHDA will be performed as described above. Theformation of a SEM graft over the skull of these mice will be performedas described above.

TABLE 1 TransSMM GCNF IP GDNF (5 nmol × 10 d) (5 nmol × 10 d)Intrastriatal 6-OHDA N = 4 N = 4 Instrastriatal SHAM N = 4 N = 4

Tyrosine-Hydroxylase (TH) Immunostaining

The brains of these mice will be fixed and processed for THimmunostaining as described by Dietz et al. (Brain Res. 1082:61-66,2006). Briefly, brains will be sectioned followed by incubation withprimary (anti-TH, 1:1000) and secondary antibodies (anti-rabbitCy3-conjugated IgG, 1:200).

Quantification of TH Immunoreactivity

Coronal sections of the rostrocaudal SN axis will be analyzed (Bregma−2.46 to −4.08). The total number of Substantia Nigra ParsCompacta-stained neurons will be counted using a superimposed grid. CSFand plasma glial cell line-derived neurotrophic factor (GDNF) levelswill be determined by enzyme-linked immunosorbent assays (ELISAs). Dataanalysis will use a one-way analysis of variance (ANOVA) and Fisher'sprotected least squares difference (PLSD) test (95% significance) formultiple comparisons.

Predicted Results

Based on prior injury models, an increased preservation of TH stainingin mice administered GDNF across the SEM graft over the skull comparedto mice administered GDNF intraperitoneally is expected in this mousemodel.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method of delivering at least onepharmaceutical agent to the central nervous system of a subject, themethod comprising directly administering at least one pharmaceuticalagent onto a semipermeable epithelial membrane (SEM) graft in the skullbase of the subject.
 2. The method of claim 1, wherein the at least onepharmaceutical agent is administered into an endonasal reservoir.
 3. Themethod of claim 1, wherein the pharmaceutical agent is administered totreat a neurological disorder or pain in the subject.
 4. The method ofclaim 1, wherein the at least one pharmaceutical agent is placed into anendonasal reservoir device in an endogenous sinus tissue of the subject,wherein the device comprises at least one opening or permeable surfaceproximal to the SEM graft in the skull base and the at least onepharmaceutical agent in the endonasal reservoir device is administeredonto the SEM graft in the skull base.
 5. The method of claim 1, furthercomprising forming a semipermeable epithelial membrane (SEM) graft inthe skull base of the subject.
 6. The method of claim 1, wherein thesubject has a neurological disorder.
 7. The method of claim 1, whereinthe subject has pain, and the pharmaceutical agent is an analgesic. 8.The method of claim 5, further comprising forming a SEM graft over anendogenous sinus tissue or in a position proximal to the SEM graft inthe skull base, where the SEM graft over the endogenous sinus tissue orin the position proximal to the SEM graft in the skull base forms anendonasal reservoir.
 9. The method of claim 5, further comprising:introducing an endonasal reservoir device comprising at least oneopening or permeable surface into an endogenous sinus tissue of thesubject; and placing the at least one pharmaceutical agent into theendonasal reservoir device; wherein the at least one opening orpermeable surface is proximal to the SEM graft in the skull base and theat least one pharmaceutical agent in the endonasal reservoir device isadministered onto the SEM graft in the skull base.
 10. The method ofclaim 1, wherein the forming, introducing, placing, or administering isperformed by an endoscopic or interfacial procedure.
 11. The method ofclaim 1, wherein the SEM graft in the skull base is formed fromsinonasal mucosa.
 12. The method of claim 1, wherein the SEM graft inthe skull base is formed in the posterior frontal table, cribiformplate/ethmoid roof, planum sphenoidale, tuberculum, sella, clivalrecess, clivus, or cervical spine.
 13. The method of claim 1, whereinthe at least one pharmaceutical agent is formulated as a component of abiodegradable biocompatible polymer.
 14. The method of claim 13, whereinthe biodegradable biocompatible polymer is cationic.
 15. The method ofclaim 13, wherein the biodegradable biocompatible polymer is a gel. 16.The method of claim 15, wherein the gel is an alginate gel, acellulose-based gel, or a chitosan-based gel.
 17. The method of claim16, wherein the alginate gel is sodium alginate.
 18. The method of claim16, wherein the cellulose-based gel is carboxymethyl cellulose orcarboxyethyl cellulose.
 19. The method of claim 16, wherein thechitosan-based gel is chitosan glycerophosphate.
 20. The method of claim1, wherein the at least one pharmaceutical agent is formulated as aliquid.
 21. The method of claim 20, wherein the liquid is athermosetting liquid.
 22. The method of any claim 1, wherein the atleast one pharmaceutical agent is administered in a sustained-releaseformulation.
 23. The method of claim 1, wherein the at least onepharmaceutical agent has a molecular size of greater than 500 Daltons,has a net negative or positive charge, or is a polar molecule.
 24. Themethod of any claim 1, wherein the at least one pharmaceutical agent isselected from the group of: an analgesic, a chemotherapeutic agent,L-DOPA, carbidopa, an anti-depressant agent, an anti-psychotic agent,donepezil, rivastigmine tartrate, galantamine, memantine, ISIS-SOD1,ISIS-SMN, ISIS-TTR, ELND005, β- or γ-secretase inhibitors, gene therapyvectors, antisense oligonucleotides, neurotrophic peptides,nanoparticles, fusion proteins, and small interfering RNAs (siRNAs).